WO2015154023A1 - Substituted spirocydic inhibitors of autotaxin - Google Patents
Substituted spirocydic inhibitors of autotaxin Download PDFInfo
- Publication number
- WO2015154023A1 WO2015154023A1 PCT/US2015/024338 US2015024338W WO2015154023A1 WO 2015154023 A1 WO2015154023 A1 WO 2015154023A1 US 2015024338 W US2015024338 W US 2015024338W WO 2015154023 A1 WO2015154023 A1 WO 2015154023A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- decan
- triazaspiro
- oxobutan
- fluoro
- Prior art date
Links
- 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 title claims description 38
- 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 title claims description 35
- 239000003112 inhibitor Substances 0.000 title claims description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 204
- 238000000034 method Methods 0.000 claims abstract description 98
- 150000003839 salts Chemical class 0.000 claims abstract description 52
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 208000004296 neuralgia Diseases 0.000 claims abstract description 15
- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 13
- 201000011510 cancer Diseases 0.000 claims abstract description 13
- 230000003176 fibrotic effect Effects 0.000 claims abstract description 12
- 206010064190 Cholestatic pruritus Diseases 0.000 claims abstract description 9
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 9
- 208000037976 chronic inflammation Diseases 0.000 claims abstract description 9
- 230000006020 chronic inflammation Effects 0.000 claims abstract description 9
- 210000004698 lymphocyte Anatomy 0.000 claims abstract description 9
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 230000001404 mediated effect Effects 0.000 claims abstract description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 204
- -1 -oxo- -CF3 Chemical group 0.000 claims description 118
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 52
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 47
- 239000005711 Benzoic acid Substances 0.000 claims description 46
- 235000010233 benzoic acid Nutrition 0.000 claims description 46
- 229920006395 saturated elastomer Polymers 0.000 claims description 45
- 125000005843 halogen group Chemical group 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 44
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 39
- 229910052760 oxygen Inorganic materials 0.000 claims description 37
- 125000005842 heteroatom Chemical group 0.000 claims description 32
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 30
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 229910052805 deuterium Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 206010016654 Fibrosis Diseases 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 230000004761 fibrosis Effects 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- GWRSATNRNFYMDI-UHFFFAOYSA-N 4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8h-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound FC=1C=C(NC=2N=C3N(C4CCCC4)CC(F)(F)C(=O)N(C)C3=CN=2)C(OC)=CC=1C(=O)NC1CCN(C)CC1 GWRSATNRNFYMDI-UHFFFAOYSA-N 0.000 claims description 8
- 102000004137 Lysophosphatidic Acid Receptors Human genes 0.000 claims description 8
- 108090000642 Lysophosphatidic Acid Receptors Proteins 0.000 claims description 8
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 claims description 7
- 206010027476 Metastases Diseases 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- QWEWLLNSJDTOKH-UHFFFAOYSA-N 1,3-thiazole-2-carboxamide Chemical compound NC(=O)C1=NC=CS1 QWEWLLNSJDTOKH-UHFFFAOYSA-N 0.000 claims description 4
- XYFFYFXZKIBNEK-OAQYLSRUSA-N C1(CCCCC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C1(CCCCC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O XYFFYFXZKIBNEK-OAQYLSRUSA-N 0.000 claims description 4
- NGJPRALBUUSWHM-RUZDIDTESA-N CCC1=CC=C(F)C(=C1)C(=O)N[C@H](C(C)C)C(=O)N1CCC2(CC1)N(CN(CC(O)=O)C2=O)C1=CC=CC=C1 Chemical compound CCC1=CC=C(F)C(=C1)C(=O)N[C@H](C(C)C)C(=O)N1CCC2(CC1)N(CN(CC(O)=O)C2=O)C1=CC=CC=C1 NGJPRALBUUSWHM-RUZDIDTESA-N 0.000 claims description 4
- FBPXBCANIWAMAK-RUZDIDTESA-N CN(CCN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)C1=CC=C(C(=O)O)C=C1)C Chemical compound CN(CCN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)C1=CC=C(C(=O)O)C=C1)C FBPXBCANIWAMAK-RUZDIDTESA-N 0.000 claims description 4
- 108010037462 Cyclooxygenase 2 Proteins 0.000 claims description 4
- GQXJQATUXRXHHZ-VCUSLETLSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F GQXJQATUXRXHHZ-VCUSLETLSA-N 0.000 claims description 4
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 claims description 4
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 4
- 108010022198 alkylglycerophosphoethanolamine phosphodiesterase Proteins 0.000 claims description 4
- 230000033115 angiogenesis Effects 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims description 4
- 229940043355 kinase inhibitor Drugs 0.000 claims description 4
- 208000002780 macular degeneration Diseases 0.000 claims description 4
- 230000009401 metastasis Effects 0.000 claims description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- UDPBOQDAZUOVNC-HSZRJFAPSA-N C(#N)C1=CC=C(CN2C(N(C(C23CCN(CC3)C([C@@H](C(C)C)NC(C3=C(C=CC(=C3)C(F)(F)F)F)=O)=O)=O)C)=O)C=C1 Chemical compound C(#N)C1=CC=C(CN2C(N(C(C23CCN(CC3)C([C@@H](C(C)C)NC(C3=C(C=CC(=C3)C(F)(F)F)F)=O)=O)=O)C)=O)C=C1 UDPBOQDAZUOVNC-HSZRJFAPSA-N 0.000 claims description 3
- GOECOLXTEALSPU-YADARESESA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)[C@H](C)OC)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)[C@H](C)OC)C1)F GOECOLXTEALSPU-YADARESESA-N 0.000 claims description 3
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 229940124639 Selective inhibitor Drugs 0.000 claims description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 201000002313 intestinal cancer Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 210000000056 organ Anatomy 0.000 claims description 3
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 3
- 208000009304 Acute Kidney Injury Diseases 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 2
- 206010005949 Bone cancer Diseases 0.000 claims description 2
- 208000018084 Bone neoplasm Diseases 0.000 claims description 2
- GIBOXIQBZGLXHE-HSZRJFAPSA-N BrC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C Chemical compound BrC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C GIBOXIQBZGLXHE-HSZRJFAPSA-N 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- JQXPNFVKZCESQZ-RUZDIDTESA-N C(#N)CN1C(N(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)C2=CC=C(C=C2)OC)=O Chemical compound C(#N)CN1C(N(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)C2=CC=C(C=C2)OC)=O JQXPNFVKZCESQZ-RUZDIDTESA-N 0.000 claims description 2
- VGXFLCRXSINQSQ-HSZRJFAPSA-N C(#N)COC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(#N)COC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O VGXFLCRXSINQSQ-HSZRJFAPSA-N 0.000 claims description 2
- RDEALTAUSNJWHE-XMMPIXPASA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C1)F RDEALTAUSNJWHE-XMMPIXPASA-N 0.000 claims description 2
- PYZWTJUUYLSWCJ-AREMUKBSSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(OCC(=O)O)C=C3)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(OCC(=O)O)C=C3)C)=O)CC2)C(C)C)C1)F PYZWTJUUYLSWCJ-AREMUKBSSA-N 0.000 claims description 2
- WHPATJXDBBZCEP-RUZDIDTESA-N C1(CCC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC=2C=C3N=CC=NC3=CC2)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O Chemical compound C1(CCC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC=2C=C3N=CC=NC3=CC2)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O WHPATJXDBBZCEP-RUZDIDTESA-N 0.000 claims description 2
- WCISFVYDMADJPX-HXUWFJFHSA-N C1(CCCC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C1(CCCC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O WCISFVYDMADJPX-HXUWFJFHSA-N 0.000 claims description 2
- CLUALAHWDCTPJK-QDOZOBACSA-N CC(C)[C@@H](NC(=O)C12CC3CC(CC(C3)C1)C2)C(=O)N1CCC2(CC1)N(CN(C)C2=O)C1=CC=C(C=C1)C(O)=O Chemical compound CC(C)[C@@H](NC(=O)C12CC3CC(CC(C3)C1)C2)C(=O)N1CCC2(CC1)N(CN(C)C2=O)C1=CC=C(C=C1)C(O)=O CLUALAHWDCTPJK-QDOZOBACSA-N 0.000 claims description 2
- BMPQFGJILDCURA-NZQKXSOJSA-N CO[C@H]([C@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)NC(C1=CC(=CC=C1)C)=O)C Chemical compound CO[C@H]([C@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)NC(C1=CC(=CC=C1)C)=O)C BMPQFGJILDCURA-NZQKXSOJSA-N 0.000 claims description 2
- 206010058019 Cancer Pain Diseases 0.000 claims description 2
- 229940122444 Chemokine receptor antagonist Drugs 0.000 claims description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- QRTLPAYPYOBWKI-OAQYLSRUSA-N ClC=1C=C(C=CC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound ClC=1C=C(C=CC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O QRTLPAYPYOBWKI-OAQYLSRUSA-N 0.000 claims description 2
- LEQGWCFLSAHFNZ-HSZRJFAPSA-N ClC=1C=C(C=CC1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C Chemical compound ClC=1C=C(C=CC1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C LEQGWCFLSAHFNZ-HSZRJFAPSA-N 0.000 claims description 2
- 208000029147 Collagen-vascular disease Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 108010037464 Cyclooxygenase 1 Proteins 0.000 claims description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 2
- FRPWXZRVHMHXCN-OAQYLSRUSA-N FC(OC=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C1)F)F Chemical compound FC(OC=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C1)F)F FRPWXZRVHMHXCN-OAQYLSRUSA-N 0.000 claims description 2
- WTDFHWLLTDTOOI-OAHLLOKOSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F WTDFHWLLTDTOOI-OAHLLOKOSA-N 0.000 claims description 2
- GCJWXMQHKZMFQY-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC(=C(C=C3)OC)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC(=C(C=C3)OC)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F GCJWXMQHKZMFQY-JOCHJYFZSA-N 0.000 claims description 2
- PDFLRDQOOPRETN-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC(=CC=C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC(=CC=C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F PDFLRDQOOPRETN-JOCHJYFZSA-N 0.000 claims description 2
- ZSNFHJFANOXLOT-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC(=CC=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC(=CC=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F ZSNFHJFANOXLOT-JOCHJYFZSA-N 0.000 claims description 2
- FNQOHPHAPZGYHQ-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC4=C(NC(O4)=O)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC4=C(NC(O4)=O)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F FNQOHPHAPZGYHQ-OAQYLSRUSA-N 0.000 claims description 2
- NZYFOHBJKUCFLW-RUZDIDTESA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OCC3COC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OCC3COC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F NZYFOHBJKUCFLW-RUZDIDTESA-N 0.000 claims description 2
- MLOHOBZHEYWWGC-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OCCO)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OCCO)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F MLOHOBZHEYWWGC-HSZRJFAPSA-N 0.000 claims description 2
- WBYXLXUXBRZQMG-LJQANCHMSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=NN(C=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=NN(C=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F WBYXLXUXBRZQMG-LJQANCHMSA-N 0.000 claims description 2
- SVIMIKSMBLUDTA-OBFZPWGMSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3CCC(CC3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3CCC(CC3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F SVIMIKSMBLUDTA-OBFZPWGMSA-N 0.000 claims description 2
- HSGKPYRCMTXDPI-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CCC(C)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CCC(C)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F HSGKPYRCMTXDPI-HXUWFJFHSA-N 0.000 claims description 2
- LLXKRJNAHLSYTL-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C=CC=C1C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C=CC=C1C LLXKRJNAHLSYTL-HSZRJFAPSA-N 0.000 claims description 2
- UIAGFPZXZVFJAN-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)S(=O)(=O)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)S(=O)(=O)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F UIAGFPZXZVFJAN-HSZRJFAPSA-N 0.000 claims description 2
- YRPBCYXITJJJIU-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=C(C=C1)C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=C(C=C1)C YRPBCYXITJJJIU-HSZRJFAPSA-N 0.000 claims description 2
- MTJUBQAUVHBHKK-HSZRJFAPSA-N FC1=C(C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=C1)C Chemical compound FC1=C(C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=C1)C MTJUBQAUVHBHKK-HSZRJFAPSA-N 0.000 claims description 2
- 102100031415 Hepatic triacylglycerol lipase Human genes 0.000 claims description 2
- 108010013563 Lipoprotein Lipase Proteins 0.000 claims description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- WFHYLAWROUXHOF-RUZDIDTESA-N N-[(1R)-1-cyclohexyl-2-(3-methyl-2,4-dioxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-2-oxoethyl]-3-methylbenzamide Chemical compound C1(CCCCC1)[C@H](C(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1)NC(C1=CC(=CC=C1)C)=O WFHYLAWROUXHOF-RUZDIDTESA-N 0.000 claims description 2
- MSXIOGSTPFCARR-JOCHJYFZSA-N N=1NN=NC1C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C Chemical compound N=1NN=NC1C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C MSXIOGSTPFCARR-JOCHJYFZSA-N 0.000 claims description 2
- DDGLAJYINOCBIE-JOCHJYFZSA-N O1COC2=C1C=CC(=C2)N2C(N(C(C21CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound O1COC2=C1C=CC(=C2)N2C(N(C(C21CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O DDGLAJYINOCBIE-JOCHJYFZSA-N 0.000 claims description 2
- LKNXEALWFBTCAW-VQIWEWKSSA-N OC(=O)C(F)(F)F.CN1CN(C2=CC=CC=C2)C2(CCN(CC2)C(=O)[C@H](NC(=O)C2=CC=CC(C)=N2)C2CCCCC2)C1=O Chemical compound OC(=O)C(F)(F)F.CN1CN(C2=CC=CC=C2)C2(CCN(CC2)C(=O)[C@H](NC(=O)C2=CC=CC(C)=N2)C2CCCCC2)C1=O LKNXEALWFBTCAW-VQIWEWKSSA-N 0.000 claims description 2
- 208000002193 Pain Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 claims description 2
- 229940122144 Prostaglandin receptor antagonist Drugs 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000012322 Raynaud phenomenon Diseases 0.000 claims description 2
- 208000033626 Renal failure acute Diseases 0.000 claims description 2
- 206010039710 Scleroderma Diseases 0.000 claims description 2
- 206010050207 Skin fibrosis Diseases 0.000 claims description 2
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 2
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 2
- 108700012920 TNF Proteins 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 201000011040 acute kidney failure Diseases 0.000 claims description 2
- 108010016133 acylglycerol kinase Proteins 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 229940035676 analgesics Drugs 0.000 claims description 2
- 239000000730 antalgic agent Substances 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 239000002559 chemokine receptor antagonist Substances 0.000 claims description 2
- 208000020832 chronic kidney disease Diseases 0.000 claims description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 239000003246 corticosteroid Substances 0.000 claims description 2
- 229960001334 corticosteroids Drugs 0.000 claims description 2
- RHJVIGLEIFVHIJ-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1[CH]CCCC1 RHJVIGLEIFVHIJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000009977 dual effect Effects 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 2
- 239000003018 immunosuppressive agent Substances 0.000 claims description 2
- 229940065725 leukotriene receptor antagonists for obstructive airway diseases Drugs 0.000 claims description 2
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims description 2
- 150000002617 leukotrienes Chemical class 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 229960003966 nicotinamide Drugs 0.000 claims description 2
- 235000005152 nicotinamide Nutrition 0.000 claims description 2
- 239000011570 nicotinamide Substances 0.000 claims description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 239000003358 phospholipase A2 inhibitor Substances 0.000 claims description 2
- XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 claims description 2
- 150000003180 prostaglandins Chemical class 0.000 claims description 2
- 229940044551 receptor antagonist Drugs 0.000 claims description 2
- 239000002464 receptor antagonist Substances 0.000 claims description 2
- 201000002793 renal fibrosis Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 claims 3
- 101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 claims 3
- XQWCVMSRUVGIQX-HSZRJFAPSA-N BrC=1C=C(C=CC1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C Chemical compound BrC=1C=C(C=CC1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C XQWCVMSRUVGIQX-HSZRJFAPSA-N 0.000 claims 1
- XVIBTKMWNLYCKN-JOCHJYFZSA-N C(#N)C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(#N)C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O XVIBTKMWNLYCKN-JOCHJYFZSA-N 0.000 claims 1
- DSWPYXJSXDRMLQ-RUZDIDTESA-N C(#N)CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)C2=CC=CC=C2 Chemical compound C(#N)CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)C2=CC=CC=C2 DSWPYXJSXDRMLQ-RUZDIDTESA-N 0.000 claims 1
- BYUJUUYDYMRQPL-AREMUKBSSA-N C(#N)COC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C Chemical compound C(#N)COC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C BYUJUUYDYMRQPL-AREMUKBSSA-N 0.000 claims 1
- PKLSBRDTQQVDFK-FDDCHVKYSA-N C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)[C@H](C)OC)C=C(C1)F Chemical compound C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)[C@H](C)OC)C=C(C1)F PKLSBRDTQQVDFK-FDDCHVKYSA-N 0.000 claims 1
- QYGDBEKYTXDNBG-GBXCKJPGSA-N C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)[C@H](C)OC)C=CC1 Chemical compound C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)[C@H](C)OC)C=CC1 QYGDBEKYTXDNBG-GBXCKJPGSA-N 0.000 claims 1
- CAMLYXXGGGUBTP-FDDCHVKYSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)[C@H](C)OC)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)[C@H](C)OC)C1)F CAMLYXXGGGUBTP-FDDCHVKYSA-N 0.000 claims 1
- UISRURNJKGWKBC-XMMPIXPASA-N C1(CC1)C(=O)NC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C1(CC1)C(=O)NC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O UISRURNJKGWKBC-XMMPIXPASA-N 0.000 claims 1
- UBCHOWVYKLDUSP-RUZDIDTESA-N C1(CC1)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=CC1 Chemical compound C1(CC1)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=CC1 UBCHOWVYKLDUSP-RUZDIDTESA-N 0.000 claims 1
- MZTDGOBVIVLPLI-XMMPIXPASA-N C1(CC1)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C1)F Chemical compound C1(CC1)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C1)F MZTDGOBVIVLPLI-XMMPIXPASA-N 0.000 claims 1
- RZGNARJWKCFBAQ-XMMPIXPASA-N C1(CC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC=2C=C3N=CC=NC3=CC2)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O Chemical compound C1(CC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC=2C=C3N=CC=NC3=CC2)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O RZGNARJWKCFBAQ-XMMPIXPASA-N 0.000 claims 1
- YOWLSYKKSDSAAN-XMMPIXPASA-N C1(CCCC1)[C@H](C(=O)N1CCC2(C(N(CN2C2=CN(C(C=C2)=O)C)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O Chemical compound C1(CCCC1)[C@H](C(=O)N1CCC2(C(N(CN2C2=CN(C(C=C2)=O)C)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O YOWLSYKKSDSAAN-XMMPIXPASA-N 0.000 claims 1
- LEQNBKIUGXBMTP-VWLOTQADSA-N CC=1C=C(C(=O)N[C@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C2CCOCC2)C=CC1 Chemical compound CC=1C=C(C(=O)N[C@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C2CCOCC2)C=CC1 LEQNBKIUGXBMTP-VWLOTQADSA-N 0.000 claims 1
- VHXSAZIFLREOKP-JOCHJYFZSA-N ClC1=C(C(=O)O)C=CC(=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C Chemical compound ClC1=C(C(=O)O)C=CC(=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C VHXSAZIFLREOKP-JOCHJYFZSA-N 0.000 claims 1
- FWQXBPDCDUMPMX-OAQYLSRUSA-N ClC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound ClC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O FWQXBPDCDUMPMX-OAQYLSRUSA-N 0.000 claims 1
- LDFRGNYZKHANFH-OAQYLSRUSA-N ClC=1C=C(C=CC1Cl)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound ClC=1C=C(C=CC1Cl)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O LDFRGNYZKHANFH-OAQYLSRUSA-N 0.000 claims 1
- UIEWINQXMGLYAY-JOCHJYFZSA-N ClC=1C=C(CN2C(N(C(C23CCN(CC3)C([C@@H](C(C)C)NC(C3=C(C=CC(=C3)C(F)(F)F)F)=O)=O)=O)C)=O)C=CC1 Chemical compound ClC=1C=C(CN2C(N(C(C23CCN(CC3)C([C@@H](C(C)C)NC(C3=C(C=CC(=C3)C(F)(F)F)F)=O)=O)=O)C)=O)C=CC1 UIEWINQXMGLYAY-JOCHJYFZSA-N 0.000 claims 1
- BHKGLCMPKLMIIW-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F BHKGLCMPKLMIIW-JOCHJYFZSA-N 0.000 claims 1
- WHVKKPNNIROQJR-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F WHVKKPNNIROQJR-JOCHJYFZSA-N 0.000 claims 1
- JVAMAQLUVPYFRN-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC=C1C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC=C1C JVAMAQLUVPYFRN-JOCHJYFZSA-N 0.000 claims 1
- OMGUNRUFPYKNOG-WZONZLPQSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)[C@@H](CC)C)C=CC=C1C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)[C@@H](CC)C)C=CC=C1C OMGUNRUFPYKNOG-WZONZLPQSA-N 0.000 claims 1
- FXWGYDPLALEKQP-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3CCOCC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3CCOCC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F FXWGYDPLALEKQP-HXUWFJFHSA-N 0.000 claims 1
- WNXSJVVSLRKTOJ-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=C4C(=NC3)NC=C4)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=C4C(=NC3)NC=C4)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F WNXSJVVSLRKTOJ-OAQYLSRUSA-N 0.000 claims 1
- ICGDCTCMAMLBLT-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=NC=CC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=NC=CC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F ICGDCTCMAMLBLT-HXUWFJFHSA-N 0.000 claims 1
- BHOCDSKRDCALBO-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC(=NC=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC(=NC=C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F BHOCDSKRDCALBO-JOCHJYFZSA-N 0.000 claims 1
- ANZLAVRNEDYVEW-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC(=NC=C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC(=NC=C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F ANZLAVRNEDYVEW-JOCHJYFZSA-N 0.000 claims 1
- MWGXXSBLEBXYHN-XMMPIXPASA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC4=C(N=C(O4)C)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC4=C(N=C(O4)C)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F MWGXXSBLEBXYHN-XMMPIXPASA-N 0.000 claims 1
- KVHCMWYGUSHGEA-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC=C(C=C3)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC=C(C=C3)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F KVHCMWYGUSHGEA-JOCHJYFZSA-N 0.000 claims 1
- SHWWECTZMNCFLG-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=NC=CC=N3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=NC=CC=N3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F SHWWECTZMNCFLG-HXUWFJFHSA-N 0.000 claims 1
- OFTYQIXWGCTZEP-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3CCOCC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3CCOCC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F OFTYQIXWGCTZEP-OAQYLSRUSA-N 0.000 claims 1
- QMXYZPVXWVDPON-XMMPIXPASA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=C4N=CC=NC4=CC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=C4N=CC=NC4=CC3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F QMXYZPVXWVDPON-XMMPIXPASA-N 0.000 claims 1
- KZRYBDLUQZFKGT-XMMPIXPASA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=CC4=C(NC(=N4)C)C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=CC4=C(NC(=N4)C)C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F KZRYBDLUQZFKGT-XMMPIXPASA-N 0.000 claims 1
- JNXAQUUKDDPRNR-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3SC=C(N3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3SC=C(N3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F JNXAQUUKDDPRNR-HXUWFJFHSA-N 0.000 claims 1
- IBXXLLHYSWPTPT-QFIPXVFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)(C)C)C=C(C=C1)C(F)(F)F IBXXLLHYSWPTPT-QFIPXVFZSA-N 0.000 claims 1
- MERXMKZCARLDQP-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)NS(=O)(=O)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)NS(=O)(=O)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F MERXMKZCARLDQP-HSZRJFAPSA-N 0.000 claims 1
- CVJFHJQGKBIOJF-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CN(C(C=C3)=O)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CN(C(C=C3)=O)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F CVJFHJQGKBIOJF-JOCHJYFZSA-N 0.000 claims 1
- IWULRNJVGTUITM-GAJHUEQPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F IWULRNJVGTUITM-GAJHUEQPSA-N 0.000 claims 1
- IWULRNJVGTUITM-UZUQRXQVSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F IWULRNJVGTUITM-UZUQRXQVSA-N 0.000 claims 1
- FUFDVMAPQXGZFO-HSZRJFAPSA-N N-[(2R)-1-[1-(1-benzofuran-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-3-methyl-1-oxobutan-2-yl]-2-fluoro-5-(trifluoromethyl)benzamide Chemical compound CC(C)[C@@H](NC(=O)c1cc(ccc1F)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)c1ccc2occc2c1 FUFDVMAPQXGZFO-HSZRJFAPSA-N 0.000 claims 1
- DBEAPVRCIGSENG-OAQYLSRUSA-N N=1NN=NC1C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound N=1NN=NC1C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O DBEAPVRCIGSENG-OAQYLSRUSA-N 0.000 claims 1
- VQJKWNQTZOTJSH-GJFSDDNBSA-N OC(=O)C(F)(F)F.CC(C)[C@@H](NC(=O)C1=C(F)C=CC(=C1)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(NC2CNC2)C=C1 Chemical compound OC(=O)C(F)(F)F.CC(C)[C@@H](NC(=O)C1=C(F)C=CC(=C1)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(NC2CNC2)C=C1 VQJKWNQTZOTJSH-GJFSDDNBSA-N 0.000 claims 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 327
- 239000000543 intermediate Substances 0.000 abstract description 6
- 238000009472 formulation Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 524
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 516
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 392
- 239000007787 solid Substances 0.000 description 384
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 373
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 339
- 239000000243 solution Substances 0.000 description 299
- 238000005160 1H NMR spectroscopy Methods 0.000 description 254
- 230000002829 reductive effect Effects 0.000 description 252
- 235000019439 ethyl acetate Nutrition 0.000 description 172
- 238000006243 chemical reaction Methods 0.000 description 143
- 239000012044 organic layer Substances 0.000 description 138
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 137
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 133
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 126
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 109
- 239000005457 ice water Substances 0.000 description 103
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 97
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 96
- 239000002904 solvent Substances 0.000 description 90
- 238000010898 silica gel chromatography Methods 0.000 description 89
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 81
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 75
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 69
- 239000003208 petroleum Substances 0.000 description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- 238000003756 stirring Methods 0.000 description 64
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- 239000003921 oil Substances 0.000 description 49
- 235000019198 oils Nutrition 0.000 description 49
- 239000007821 HATU Substances 0.000 description 48
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 43
- 238000001914 filtration Methods 0.000 description 40
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 35
- 238000004809 thin layer chromatography Methods 0.000 description 35
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 30
- 238000000746 purification Methods 0.000 description 30
- WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 description 28
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 28
- 239000002244 precipitate Substances 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
- 238000010791 quenching Methods 0.000 description 25
- 230000000171 quenching effect Effects 0.000 description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 24
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 24
- 239000012065 filter cake Substances 0.000 description 24
- 239000012312 sodium hydride Substances 0.000 description 24
- 229910000104 sodium hydride Inorganic materials 0.000 description 24
- 239000000725 suspension Substances 0.000 description 23
- HTUHXGLKWIWJTR-SNVBAGLBSA-N (2r)-2-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]-3-methylbutanoic acid Chemical compound CC(C)[C@H](C(O)=O)NC(=O)C1=CC(C(F)(F)F)=CC=C1F HTUHXGLKWIWJTR-SNVBAGLBSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 20
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 20
- 238000002953 preparative HPLC Methods 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 235000019270 ammonium chloride Nutrition 0.000 description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 239000012298 atmosphere Substances 0.000 description 12
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 11
- 150000001721 carbon Chemical group 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000012279 sodium borohydride Substances 0.000 description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 8
- YRCGAHTZOXPQPR-UHFFFAOYSA-N 2-ethylnonanoic acid Chemical compound CCCCCCCC(CC)C(O)=O YRCGAHTZOXPQPR-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- PDKXJKWLFFZPPF-UHFFFAOYSA-N [dimethylamino-(3-oxidotriazolo[4,5-b]pyridin-3-ium-1-yl)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(C(N(C)C)=[N+](C)C)N=[N+]([O-])C2=N1 PDKXJKWLFFZPPF-UHFFFAOYSA-N 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 6
- JXHYCCGOZUGBFD-UHFFFAOYSA-N benzoic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=CC=C1 JXHYCCGOZUGBFD-UHFFFAOYSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000004296 chiral HPLC Methods 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 5
- ALBOFFXGHBTZSA-LLVKDONJSA-N (2r)-2-[(2-fluoro-3-methylbenzoyl)amino]-3-methylbutanoic acid Chemical compound CC(C)[C@H](C(O)=O)NC(=O)C1=CC=CC(C)=C1F ALBOFFXGHBTZSA-LLVKDONJSA-N 0.000 description 4
- HOFUGGFJBSCHEW-UHFFFAOYSA-N (4-prop-2-enoxyphenyl)boronic acid Chemical compound OB(O)C1=CC=C(OCC=C)C=C1 HOFUGGFJBSCHEW-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- YXTBPQNTBMEZTB-GFCCVEGCSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)O)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)O)C(C)C)C1)F YXTBPQNTBMEZTB-GFCCVEGCSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- IZKYDFLRAAPPQE-CQSZACIVSA-N (2R)-2-cyclohexyl-2-[(3-methylbenzoyl)amino]acetic acid Chemical compound C1(CCCCC1)[C@H](C(=O)O)NC(C1=CC(=CC=C1)C)=O IZKYDFLRAAPPQE-CQSZACIVSA-N 0.000 description 3
- HODWPRQQRJVYGG-LLVKDONJSA-N (2r)-3-methyl-2-[(3-methylbenzoyl)amino]butanoic acid Chemical compound CC(C)[C@H](C(O)=O)NC(=O)C1=CC=CC(C)=C1 HODWPRQQRJVYGG-LLVKDONJSA-N 0.000 description 3
- GUMINBOCIUCMJL-UHFFFAOYSA-N (3-phenylmethoxycyclobutyl)methanol Chemical compound C1C(CO)CC1OCC1=CC=CC=C1 GUMINBOCIUCMJL-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- IAWQUHCVFXQBMC-UHFFFAOYSA-N 1,3-benzoxazol-5-amine Chemical compound NC1=CC=C2OC=NC2=C1 IAWQUHCVFXQBMC-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- RYCNUMLMNKHWPZ-SNVBAGLBSA-N 1-acetyl-sn-glycero-3-phosphocholine Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C RYCNUMLMNKHWPZ-SNVBAGLBSA-N 0.000 description 3
- QBAYIBZITZBSFO-UHFFFAOYSA-N 2-(trifluoromethyl)benzamide Chemical compound NC(=O)C1=CC=CC=C1C(F)(F)F QBAYIBZITZBSFO-UHFFFAOYSA-N 0.000 description 3
- IFYWBEDKWLNJTM-UHFFFAOYSA-N 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;hydrochloride Chemical compound Cl.C1CNCCC21C(=O)N(C)CN2C1=CC=CC=C1 IFYWBEDKWLNJTM-UHFFFAOYSA-N 0.000 description 3
- YHOYYHYBFSYOSQ-UHFFFAOYSA-N 3-methylbenzoyl chloride Chemical compound CC1=CC=CC(C(Cl)=O)=C1 YHOYYHYBFSYOSQ-UHFFFAOYSA-N 0.000 description 3
- MNEOLRFGVQZMLA-UHFFFAOYSA-N 5-nitro-1,3-benzoxazole Chemical compound [O-][N+](=O)C1=CC=C2OC=NC2=C1 MNEOLRFGVQZMLA-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- BWSIWBLHEPRLRT-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)NC(=O)OC)=O)C)=O)CC1 Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)NC(=O)OC)=O)C)=O)CC1 BWSIWBLHEPRLRT-UHFFFAOYSA-N 0.000 description 3
- DAYRLROUUVCIQC-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)[N+](=O)[O-])=O)C)=O)CC1 Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)[N+](=O)[O-])=O)C)=O)CC1 DAYRLROUUVCIQC-UHFFFAOYSA-N 0.000 description 3
- NYLKTDGFIYPAJX-JOCHJYFZSA-N CC=1C=C(C(=O)N[C@@H](C(N2CCC3(COC(N3C3=CC=CC=C3)=O)CC2)=O)C(C)C)C=CC1 Chemical compound CC=1C=C(C(=O)N[C@@H](C(N2CCC3(COC(N3C3=CC=CC=C3)=O)CC2)=O)C(C)C)C=CC1 NYLKTDGFIYPAJX-JOCHJYFZSA-N 0.000 description 3
- WNGGVNLXXCHXLF-UHFFFAOYSA-N CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C=C2)NC2COC2 Chemical compound CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C=C2)NC2COC2 WNGGVNLXXCHXLF-UHFFFAOYSA-N 0.000 description 3
- REXZRKVSHFOVJY-CYBMUJFWSA-N COC([C@@H](C(C)C)NC(C1=C(C=CC(=C1)CC)F)=O)=O Chemical compound COC([C@@H](C(C)C)NC(C1=C(C=CC(=C1)CC)F)=O)=O REXZRKVSHFOVJY-CYBMUJFWSA-N 0.000 description 3
- VOLSRGHOVRKEKR-UHFFFAOYSA-N Cl.BrC1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C Chemical compound Cl.BrC1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C VOLSRGHOVRKEKR-UHFFFAOYSA-N 0.000 description 3
- BOVRBJIKOACTQN-UHFFFAOYSA-N Cl.C(C)OC(CN1CN(C2(C1=O)CCNCC2)C2=CC=CC=C2)=O Chemical compound Cl.C(C)OC(CN1CN(C2(C1=O)CCNCC2)C2=CC=CC=C2)=O BOVRBJIKOACTQN-UHFFFAOYSA-N 0.000 description 3
- PKIJKKJZABCKII-UHFFFAOYSA-N Cl.C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)=O)=O Chemical compound Cl.C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)=O)=O PKIJKKJZABCKII-UHFFFAOYSA-N 0.000 description 3
- PDAHLAFJCZBDJG-UHFFFAOYSA-N Cl.C1(CCCCC1)N1C(N(C(C12CCNCC2)=O)C)=O Chemical compound Cl.C1(CCCCC1)N1C(N(C(C12CCNCC2)=O)C)=O PDAHLAFJCZBDJG-UHFFFAOYSA-N 0.000 description 3
- QQRJKHSCUCGNAH-UHFFFAOYSA-N Cl.CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C#N)C=C2 Chemical compound Cl.CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C#N)C=C2 QQRJKHSCUCGNAH-UHFFFAOYSA-N 0.000 description 3
- GQTZDMZZQXXADN-UHFFFAOYSA-N Cl.COC1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)C Chemical compound Cl.COC1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)C GQTZDMZZQXXADN-UHFFFAOYSA-N 0.000 description 3
- CAKQNJGHSUJCEV-UHFFFAOYSA-N Cl.N=1NN=NC1C1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)=O Chemical compound Cl.N=1NN=NC1C1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)=O CAKQNJGHSUJCEV-UHFFFAOYSA-N 0.000 description 3
- AEOGPETYCDHTTQ-UHFFFAOYSA-N Cl.O1C=NC2=C1C=CC(=C2)N2C(N(C(C21CCNCC1)=O)C)=O Chemical compound Cl.O1C=NC2=C1C=CC(=C2)N2C(N(C(C21CCNCC1)=O)C)=O AEOGPETYCDHTTQ-UHFFFAOYSA-N 0.000 description 3
- YIHKQVVAQIJGNW-MUTAZJQDSA-N Cl.[2H]C([2H])([2H])Oc1ccc(cc1)N1C(=O)N(C)C(=O)C11CCNCC1 Chemical compound Cl.[2H]C([2H])([2H])Oc1ccc(cc1)N1C(=O)N(C)C(=O)C11CCNCC1 YIHKQVVAQIJGNW-MUTAZJQDSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- HGOPYEWWZGZVJI-UHFFFAOYSA-N benzyl 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C1CC2(C(NC(=O)N2)=O)CCN1C(=O)OCC1=CC=CC=C1 HGOPYEWWZGZVJI-UHFFFAOYSA-N 0.000 description 3
- GUXRKOGGQHNTIY-UHFFFAOYSA-N benzyl 3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2)=O)C)=O)CC1 GUXRKOGGQHNTIY-UHFFFAOYSA-N 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- LDZCACILIBPLQU-GFCCVEGCSA-N methyl (2R)-3-methyl-2-[(3-methylbenzoyl)amino]butanoate Chemical compound COC([C@@H](C(C)C)NC(C1=CC(=CC=C1)C)=O)=O LDZCACILIBPLQU-GFCCVEGCSA-N 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- PZAOANXPKWANOY-LLVKDONJSA-N (2R)-2-[(3-fluoro-5-methylbenzoyl)amino]-3-methylbutanoic acid Chemical compound FC=1C=C(C(=O)N[C@@H](C(=O)O)C(C)C)C=C(C1)C PZAOANXPKWANOY-LLVKDONJSA-N 0.000 description 2
- LQLGKCHDVVPGRT-UHFFFAOYSA-N (3-phenylmethoxycyclobutyl)methyl methanesulfonate Chemical compound C1C(COS(=O)(=O)C)CC1OCC1=CC=CC=C1 LQLGKCHDVVPGRT-UHFFFAOYSA-N 0.000 description 2
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 description 2
- KSQLNMJXRMQLEG-UHFFFAOYSA-N 1-benzyl-4-(cyclopropylmethylamino)piperidine-4-carbonitrile Chemical compound C1CC(C#N)(NCC2CC2)CCN1CC1=CC=CC=C1 KSQLNMJXRMQLEG-UHFFFAOYSA-N 0.000 description 2
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 2
- NNJSDVWFUJMHSO-UHFFFAOYSA-N 5-ethyl-2-fluorobenzoic acid Chemical compound CCC1=CC=C(F)C(C(O)=O)=C1 NNJSDVWFUJMHSO-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- DOFZLTZQMVGCLP-HSZRJFAPSA-N BrC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C(=CC=C2)C)F)=O)=O)=O)C Chemical compound BrC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C(=CC=C2)C)F)=O)=O)=O)C DOFZLTZQMVGCLP-HSZRJFAPSA-N 0.000 description 2
- BVYYDEKYMCUJBZ-XMMPIXPASA-N C(#N)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C(=CC=C2)C)F)=O)=O)=O)C Chemical compound C(#N)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C(=CC=C2)C)F)=O)=O)=O)C BVYYDEKYMCUJBZ-XMMPIXPASA-N 0.000 description 2
- KTOMLKZVNNYBLC-AREMUKBSSA-N C(C)OC(CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC(=C2)C)F)=O)=O)C2=CC=CC=C2)=O Chemical compound C(C)OC(CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC(=C2)C)F)=O)=O)C2=CC=CC=C2)=O KTOMLKZVNNYBLC-AREMUKBSSA-N 0.000 description 2
- VNOMDZYUHYQSCO-MUUNZHRXSA-N C(C)OC(COC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C)=O Chemical compound C(C)OC(COC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C)=O VNOMDZYUHYQSCO-MUUNZHRXSA-N 0.000 description 2
- OLKPUYYYNAVLGE-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)N)=O)C)=O)CC1 Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)N)=O)C)=O)CC1 OLKPUYYYNAVLGE-UHFFFAOYSA-N 0.000 description 2
- YEQXRRNUXJHGEH-MUUNZHRXSA-N C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O)=O Chemical compound C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O)=O YEQXRRNUXJHGEH-MUUNZHRXSA-N 0.000 description 2
- KPYNEPNUIWWVBW-RUZDIDTESA-N COC(C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)CCN(C)C)=O)=O Chemical compound COC(C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)CCN(C)C)=O)=O KPYNEPNUIWWVBW-RUZDIDTESA-N 0.000 description 2
- UXUBGTXSWGYPQI-UHFFFAOYSA-N Cl.C(C)OC(COC1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C)=O Chemical compound Cl.C(C)OC(COC1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C)=O UXUBGTXSWGYPQI-UHFFFAOYSA-N 0.000 description 2
- AIPKEPCUXGMQEE-UHFFFAOYSA-N Cl.C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCNCC2)=O)C)=O Chemical compound Cl.C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCNCC2)=O)C)=O AIPKEPCUXGMQEE-UHFFFAOYSA-N 0.000 description 2
- PBVNMJPEZBMLMD-UHFFFAOYSA-N Cl.C1(=CC=CC=C1)N1C(OCC12CCNCC2)=O Chemical compound Cl.C1(=CC=CC=C1)N1C(OCC12CCNCC2)=O PBVNMJPEZBMLMD-UHFFFAOYSA-N 0.000 description 2
- ZIIJERLVLBETKE-UHFFFAOYSA-N Cl.CC1N(C2(C(N1C)=O)CCNCC2)C2=CC=C(C(=O)OCC1=CC=CC=C1)C=C2 Chemical compound Cl.CC1N(C2(C(N1C)=O)CCNCC2)C2=CC=C(C(=O)OCC1=CC=CC=C1)C=C2 ZIIJERLVLBETKE-UHFFFAOYSA-N 0.000 description 2
- CJVWOXHLAZETRN-UHFFFAOYSA-N Cl.CN(CCN1CN(C2(C1=O)CCNCC2)C2=CC=C(C(=O)OC)C=C2)C Chemical compound Cl.CN(CCN1CN(C2(C1=O)CCNCC2)C2=CC=C(C(=O)OC)C=C2)C CJVWOXHLAZETRN-UHFFFAOYSA-N 0.000 description 2
- YISYEKGFDVXRFR-UHFFFAOYSA-N Cl.CN1C(N(C2(C1=O)CCNCC2)C2=CC=C(C=C2)[N+](=O)[O-])=O Chemical compound Cl.CN1C(N(C2(C1=O)CCNCC2)C2=CC=C(C=C2)[N+](=O)[O-])=O YISYEKGFDVXRFR-UHFFFAOYSA-N 0.000 description 2
- XKPZXXVIAFDYCT-UHFFFAOYSA-N Cl.COC1CCC(CC1)N1C(N(C(C12CCNCC2)=O)C)=O Chemical compound Cl.COC1CCC(CC1)N1C(N(C(C12CCNCC2)=O)C)=O XKPZXXVIAFDYCT-UHFFFAOYSA-N 0.000 description 2
- AIMYLSTYNUSWOF-UHFFFAOYSA-N Cl.N1N=C(N=C1)C1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C Chemical compound Cl.N1N=C(N=C1)C1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C AIMYLSTYNUSWOF-UHFFFAOYSA-N 0.000 description 2
- BUQUATZPZHRSFL-UHFFFAOYSA-N Cl.N1N=CC2=CC(=CC=C12)N1CN(C(C12CCNCC2)=O)C Chemical compound Cl.N1N=CC2=CC(=CC=C12)N1CN(C(C12CCNCC2)=O)C BUQUATZPZHRSFL-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- CWSQVYFGLYCBFT-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F CWSQVYFGLYCBFT-OAQYLSRUSA-N 0.000 description 2
- FNWFYYUCVVMUMO-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=NC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=NC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F FNWFYYUCVVMUMO-HXUWFJFHSA-N 0.000 description 2
- WVJFJUVNPHYXQD-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=[N+](C=C3)[O-])=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=[N+](C=C3)[O-])=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F WVJFJUVNPHYXQD-HXUWFJFHSA-N 0.000 description 2
- FDAWOYJCBVRUDO-QYGXFBIXSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3CC(C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3CC(C3)OC)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F FDAWOYJCBVRUDO-QYGXFBIXSA-N 0.000 description 2
- QJCCUDVULRJUPE-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)B(O)O)C)=O)CC2)C(C)C)C=CC=C1C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)B(O)O)C)=O)CC2)C(C)C)C=CC=C1C QJCCUDVULRJUPE-HSZRJFAPSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 208000028389 Nerve injury Diseases 0.000 description 2
- 102000009609 Pyrophosphatases Human genes 0.000 description 2
- 108010009413 Pyrophosphatases Proteins 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 2
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 2
- SNIABFMMCKVXSY-UHFFFAOYSA-N benzoylazanium;chloride Chemical compound Cl.NC(=O)C1=CC=CC=C1 SNIABFMMCKVXSY-UHFFFAOYSA-N 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- MCXBIZXYNQHVCM-UHFFFAOYSA-N decan-4-one;hydrochloride Chemical compound Cl.CCCCCCC(=O)CCC MCXBIZXYNQHVCM-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 2
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- LZXXNPOYQCLXRS-UHFFFAOYSA-N methyl 4-aminobenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1 LZXXNPOYQCLXRS-UHFFFAOYSA-N 0.000 description 2
- HQTPWERZTKULDL-UHFFFAOYSA-N methyl N-[4-(3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-1-yl)phenyl]carbamate Chemical compound COC(NC1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)C)=O)=O HQTPWERZTKULDL-UHFFFAOYSA-N 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000000644 propagated effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- WAMWSIDTKSNDCU-SSDOTTSWSA-N (2r)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@H](N)C1CCCCC1 WAMWSIDTKSNDCU-SSDOTTSWSA-N 0.000 description 1
- SZXBQTSZISFIAO-SSDOTTSWSA-N (2r)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-SSDOTTSWSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- UKGJZDSUJSPAJL-YPUOHESYSA-N (e)-n-[(1r)-1-[3,5-difluoro-4-(methanesulfonamido)phenyl]ethyl]-3-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]prop-2-enamide Chemical compound CCCC1=NC(C(F)(F)F)=CC=C1\C=C\C(=O)N[C@H](C)C1=CC(F)=C(NS(C)(=O)=O)C(F)=C1 UKGJZDSUJSPAJL-YPUOHESYSA-N 0.000 description 1
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 1
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 1
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- FBRJYBGLCHWYOE-UHFFFAOYSA-N 2-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(F)(F)F FBRJYBGLCHWYOE-UHFFFAOYSA-N 0.000 description 1
- VLZVIIYRNMWPSN-UHFFFAOYSA-N 2-Amino-4-nitrophenol Chemical compound NC1=CC([N+]([O-])=O)=CC=C1O VLZVIIYRNMWPSN-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- DGNAETGARNTCIL-UHFFFAOYSA-N 2-fluoro-3-methylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1F DGNAETGARNTCIL-UHFFFAOYSA-N 0.000 description 1
- LIFKXWNFWIUMJT-UHFFFAOYSA-N 2-fluoro-5-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC(C(F)(F)F)=CC=C1F LIFKXWNFWIUMJT-UHFFFAOYSA-N 0.000 description 1
- XXUNIGZDNWWYED-UHFFFAOYSA-N 2-methylbenzamide Chemical compound CC1=CC=CC=C1C(N)=O XXUNIGZDNWWYED-UHFFFAOYSA-N 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- YGYGASJNJTYNOL-CQSZACIVSA-N 3-[(4r)-2,2-dimethyl-1,1-dioxothian-4-yl]-5-(4-fluorophenyl)-1h-indole-7-carboxamide Chemical compound C1CS(=O)(=O)C(C)(C)C[C@@H]1C1=CNC2=C(C(N)=O)C=C(C=3C=CC(F)=CC=3)C=C12 YGYGASJNJTYNOL-CQSZACIVSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- XPUFVYIUPYNLPD-UHFFFAOYSA-N 3-fluoro-5-methylbenzoic acid Chemical compound CC1=CC(F)=CC(C(O)=O)=C1 XPUFVYIUPYNLPD-UHFFFAOYSA-N 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- LAJFUJQONZNLBD-UHFFFAOYSA-N 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound C1CNCCC21C(=O)N(C)C(=O)N2C1=CC=CC=C1 LAJFUJQONZNLBD-UHFFFAOYSA-N 0.000 description 1
- IPBXLTHOJUWUIJ-UHFFFAOYSA-N 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;hydrochloride Chemical compound Cl.C1CNCCC21C(=O)N(C)C(=O)N2C1=CC=CC=C1 IPBXLTHOJUWUIJ-UHFFFAOYSA-N 0.000 description 1
- ROADCYAOHVSOLQ-UHFFFAOYSA-N 3-oxetanone Chemical compound O=C1COC1 ROADCYAOHVSOLQ-UHFFFAOYSA-N 0.000 description 1
- YNNOFVDQHAHVFG-UHFFFAOYSA-N 3-phenylmethoxycyclobutane-1-carboxylic acid Chemical compound C1C(C(=O)O)CC1OCC1=CC=CC=C1 YNNOFVDQHAHVFG-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- UMLFTCYAQPPZER-UHFFFAOYSA-N 4-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=C(C#N)C=C1 UMLFTCYAQPPZER-UHFFFAOYSA-N 0.000 description 1
- VJPPLCNBDLZIFG-ZDUSSCGKSA-N 4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Chemical compound C(C#CC)(=O)N[C@@H]1CN(CCC1)C1=C2C(=C(NC2=C(C=C1F)C(=O)N)C)C VJPPLCNBDLZIFG-ZDUSSCGKSA-N 0.000 description 1
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 1
- XYWIPYBIIRTJMM-IBGZPJMESA-N 4-[[(2S)-2-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-5-methoxy-2-oxopyridin-1-yl]butanoyl]amino]-2-fluorobenzamide Chemical compound CC[C@H](N1C=C(OC)C(=CC1=O)C1=C(C=CC(Cl)=C1)N1C=C(N=N1)C(F)(F)F)C(=O)NC1=CC(F)=C(C=C1)C(N)=O XYWIPYBIIRTJMM-IBGZPJMESA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 description 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 1
- IJIBRSFAXRFPPN-UHFFFAOYSA-N 5-bromo-2-methoxybenzaldehyde Chemical compound COC1=CC=C(Br)C=C1C=O IJIBRSFAXRFPPN-UHFFFAOYSA-N 0.000 description 1
- OGGLMNLWYAICPS-VCUSLETLSA-N 5-ethyl-2-fluoro-N-[(2R)-3-methoxy-1-[1-(4-methoxyphenyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl]-1-oxobutan-2-yl]benzamide Chemical compound CCC1=CC=C(F)C(=C1)C(=O)N[C@H](C(C)OC)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(OC)C=C1 OGGLMNLWYAICPS-VCUSLETLSA-N 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- STLPJYGZOIEDAJ-UHFFFAOYSA-N 6-amino-3h-1,3-benzoxazol-2-one Chemical compound NC1=CC=C2NC(=O)OC2=C1 STLPJYGZOIEDAJ-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- YRKMNVBGGPUPLY-UHFFFAOYSA-N Br.C(C)N1C(N(C2(C1=O)CCNCC2)CC2=CC=C(C#N)C=C2)=O Chemical compound Br.C(C)N1C(N(C2(C1=O)CCNCC2)CC2=CC=C(C#N)C=C2)=O YRKMNVBGGPUPLY-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- GPAQFTVLRMRQPG-JOCHJYFZSA-N C(#N)C=1C=C(C=CC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(#N)C=1C=C(C=CC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O GPAQFTVLRMRQPG-JOCHJYFZSA-N 0.000 description 1
- MBAPDORGNGYDFP-OAQYLSRUSA-N C(C)(=O)N1CC(C1)CN1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(C)(=O)N1CC(C1)CN1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O MBAPDORGNGYDFP-OAQYLSRUSA-N 0.000 description 1
- AJASGMZXUFJNGO-AREMUKBSSA-N C(C)(=O)NC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C Chemical compound C(C)(=O)NC1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C AJASGMZXUFJNGO-AREMUKBSSA-N 0.000 description 1
- WDTOENJUPDDZAF-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(C(N)=O)NC1=CC=C(C=C1)Br Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(C(N)=O)NC1=CC=C(C=C1)Br WDTOENJUPDDZAF-UHFFFAOYSA-N 0.000 description 1
- MMNWNPBLZSZYBH-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC(=NC=C1)OC)C(N)=O Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC(=NC=C1)OC)C(N)=O MMNWNPBLZSZYBH-UHFFFAOYSA-N 0.000 description 1
- YGNGSBREWOHUMA-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)C(=O)OC)C#N Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(NC1=CC=C(C=C1)C(=O)OC)C#N YGNGSBREWOHUMA-UHFFFAOYSA-N 0.000 description 1
- ZJHMHNHHAHOXCB-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2CC2CC(C2)O)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(C(N2CC2CC(C2)O)=O)C)=O)CC1 ZJHMHNHHAHOXCB-UHFFFAOYSA-N 0.000 description 1
- QUNSWIHCZYWEFI-BUVRLJJBSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(/N=C/N(C)C)=O)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C(/N=C/N(C)C)=O)C)=O)CC1 QUNSWIHCZYWEFI-BUVRLJJBSA-N 0.000 description 1
- SUJOJJFVULOWHX-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C2=NNC=N2)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)C2=NNC=N2)C)=O)CC1 SUJOJJFVULOWHX-UHFFFAOYSA-N 0.000 description 1
- HWRPPENWMLJOEM-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)OCC(=O)OCC)C)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(N(CN2C2=CC=C(C=C2)OCC(=O)OCC)C)=O)CC1 HWRPPENWMLJOEM-UHFFFAOYSA-N 0.000 description 1
- FSQBKIVHXLJAAA-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C=2C=CC3=C(N=CO3)C2)=O)=O)CC1 Chemical compound C(C)(C)(C)OC(=O)N1CCC2(C(NC(N2C=2C=CC3=C(N=CO3)C2)=O)=O)CC1 FSQBKIVHXLJAAA-UHFFFAOYSA-N 0.000 description 1
- GEEZBLRRRGCWAR-TVKKRMFBSA-N C(C)C([C@H](C(=O)O)NC(C1=CC(=CC=C1)C)=O)C Chemical compound C(C)C([C@H](C(=O)O)NC(C1=CC(=CC=C1)C)=O)C GEEZBLRRRGCWAR-TVKKRMFBSA-N 0.000 description 1
- XYZFYBDUACTQKS-HSZRJFAPSA-N C(C)C=1C(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC1)F Chemical compound C(C)C=1C(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC1)F XYZFYBDUACTQKS-HSZRJFAPSA-N 0.000 description 1
- FMNDIMBGVSQAPI-AREMUKBSSA-N C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C2CCOCC2)C=CC1 Chemical compound C(C)C=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C2CCOCC2)C=CC1 FMNDIMBGVSQAPI-AREMUKBSSA-N 0.000 description 1
- GJGLRORVXVDGLT-XMMPIXPASA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)=O)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)OC)=O)C)=O)CC2)C(C)C)C1)F GJGLRORVXVDGLT-XMMPIXPASA-N 0.000 description 1
- RTIHBKINNPLROJ-HSZRJFAPSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C1)F RTIHBKINNPLROJ-HSZRJFAPSA-N 0.000 description 1
- CSUDRQYUGZFSQX-XMMPIXPASA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CN(C(C=C3)=O)C)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CN(C(C=C3)=O)C)C)=O)CC2)C(C)C)C1)F CSUDRQYUGZFSQX-XMMPIXPASA-N 0.000 description 1
- KIYAHTYTVMZFTM-UQBPGWFLSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C1)F KIYAHTYTVMZFTM-UQBPGWFLSA-N 0.000 description 1
- KIYAHTYTVMZFTM-KBMIEXCESA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N([C@H](N3C3=CC=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C1)F KIYAHTYTVMZFTM-KBMIEXCESA-N 0.000 description 1
- UMUSRQDHGFIKBG-VCUSLETLSA-N C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(NC(N3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C1)F Chemical compound C(C)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(NC(N3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C1)F UMUSRQDHGFIKBG-VCUSLETLSA-N 0.000 description 1
- JVTNMLIYHXJHRM-QGZVFWFLSA-N C(C)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(C)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O JVTNMLIYHXJHRM-QGZVFWFLSA-N 0.000 description 1
- YUSDSOYUABSFOB-HSZRJFAPSA-N C(C)OC(NC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O)=O Chemical compound C(C)OC(NC1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O)=O YUSDSOYUABSFOB-HSZRJFAPSA-N 0.000 description 1
- FEEIXHTXTABLRV-JOCHJYFZSA-N C(C1=CC=CC=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(C1=CC=CC=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O FEEIXHTXTABLRV-JOCHJYFZSA-N 0.000 description 1
- GRIZPACFGLDLIG-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)O)=O)C)=O)CC1 Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2C2=CC=C(C=C2)O)=O)C)=O)CC1 GRIZPACFGLDLIG-UHFFFAOYSA-N 0.000 description 1
- LFYKFDTWFWSDGN-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2CC2=CC=C(C=C2)C#N)=O)C)=O)CC1 Chemical compound C(C1=CC=CC=C1)OC(=O)N1CCC2(C(N(C(N2CC2=CC=C(C=C2)C#N)=O)C)=O)CC1 LFYKFDTWFWSDGN-UHFFFAOYSA-N 0.000 description 1
- YIPKBYQEYHKEHN-MUUNZHRXSA-N C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=NC=CC=C2)=O)=O)=O)C)=O Chemical compound C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=NC=CC=C2)=O)=O)=O)C)=O YIPKBYQEYHKEHN-MUUNZHRXSA-N 0.000 description 1
- DNQCOHUOAHQAOD-YNKGCYCKSA-N C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C)C)=O Chemical compound C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)CC)F)=O)=O)=O)C)C)=O DNQCOHUOAHQAOD-YNKGCYCKSA-N 0.000 description 1
- IMDCEXZKOIPWHX-GDLZYMKVSA-N C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O IMDCEXZKOIPWHX-GDLZYMKVSA-N 0.000 description 1
- WNZZCFYRMROUMP-HSZRJFAPSA-N C(N)(=O)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C(=CC=C2)C)F)=O)=O)=O)C Chemical compound C(N)(=O)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C(=CC=C2)C)F)=O)=O)=O)C WNZZCFYRMROUMP-HSZRJFAPSA-N 0.000 description 1
- RIBHIMIYEIPLAE-JOCHJYFZSA-N C(N)(=O)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C Chemical compound C(N)(=O)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C RIBHIMIYEIPLAE-JOCHJYFZSA-N 0.000 description 1
- LMBIYMSSVZDHLJ-XMMPIXPASA-N C1(CC1)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C1)F Chemical compound C1(CC1)C=1C=CC(=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C(=O)O)C=C3)=O)C)=O)CC2)C(C)C)C1)F LMBIYMSSVZDHLJ-XMMPIXPASA-N 0.000 description 1
- GNLVIJDIHHCHMW-LJQANCHMSA-N C1(CC1)CN1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C1(CC1)CN1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O GNLVIJDIHHCHMW-LJQANCHMSA-N 0.000 description 1
- RHGOOCOZFJUGBH-GOSISDBHSA-N C1(CC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound C1(CC1)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O RHGOOCOZFJUGBH-GOSISDBHSA-N 0.000 description 1
- GZJQPKPODOFAKS-RUZDIDTESA-N C1(CCCC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC2=CC=3N(C=C2)N=C(N3)C)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O Chemical compound C1(CCCC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC2=CC=3N(C=C2)N=C(N3)C)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O GZJQPKPODOFAKS-RUZDIDTESA-N 0.000 description 1
- AVCLPPIOIMVHKM-AREMUKBSSA-N C1(CCCC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC=2C=C3N=CC=NC3=CC2)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O Chemical compound C1(CCCC1)[C@H](C(=O)N1CCC2(C(N(C(N2CC=2C=C3N=CC=NC3=CC2)=O)C)=O)CC1)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O AVCLPPIOIMVHKM-AREMUKBSSA-N 0.000 description 1
- GDGRYKTUQLSQOO-XMMPIXPASA-N CC(C)[C@@H](NC(=O)c1cc(ccc1F)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(CCN(C)C)C2=O)c1ccc(cc1)C(O)=O Chemical compound CC(C)[C@@H](NC(=O)c1cc(ccc1F)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(CCN(C)C)C2=O)c1ccc(cc1)C(O)=O GDGRYKTUQLSQOO-XMMPIXPASA-N 0.000 description 1
- YVWMYJOXTKDKMW-OAQYLSRUSA-N CC([C@H](C(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)C Chemical compound CC([C@H](C(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)C YVWMYJOXTKDKMW-OAQYLSRUSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- NSBSPXKDMKAISE-XMMPIXPASA-N CN(C(C1=CC(=CC=C1)C)=O)[C@@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)C(C)C Chemical compound CN(C(C1=CC(=CC=C1)C)=O)[C@@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)C(C)C NSBSPXKDMKAISE-XMMPIXPASA-N 0.000 description 1
- HZDDNNJFFAHLIL-MRXNPFEDSA-N CN1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound CN1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O HZDDNNJFFAHLIL-MRXNPFEDSA-N 0.000 description 1
- WFANAJYZARCOSJ-UHFFFAOYSA-N CN1C(N(C2(C1=O)CCNCC2)CC2=CC=C(C#N)C=C2)=O Chemical compound CN1C(N(C2(C1=O)CCNCC2)CC2=CC=C(C#N)C=C2)=O WFANAJYZARCOSJ-UHFFFAOYSA-N 0.000 description 1
- HIDNZZJXDDHNIT-HSZRJFAPSA-N CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)C)=O)=O)C2=CC=C(C(=O)O)C=C2 Chemical compound CN1CN(C2(C1=O)CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)C)=O)=O)C2=CC=C(C(=O)O)C=C2 HIDNZZJXDDHNIT-HSZRJFAPSA-N 0.000 description 1
- QAERKTUSUHHSGT-UHFFFAOYSA-N COC(C(C1CCOCC1)NC(C1=CC(=CC=C1)C)=O)=O Chemical compound COC(C(C1CCOCC1)NC(C1=CC(=CC=C1)C)=O)=O QAERKTUSUHHSGT-UHFFFAOYSA-N 0.000 description 1
- KTXSXZPBZJDAMC-AREMUKBSSA-N COC(C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)CCN(C)C)=O Chemical compound COC(C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)CCN(C)C)=O KTXSXZPBZJDAMC-AREMUKBSSA-N 0.000 description 1
- DDLODZNYRISUEJ-GFCCVEGCSA-N COC([C@@H](C(C)C)NC(C1=C(C(=CC=C1)C)F)=O)=O Chemical compound COC([C@@H](C(C)C)NC(C1=C(C(=CC=C1)C)F)=O)=O DDLODZNYRISUEJ-GFCCVEGCSA-N 0.000 description 1
- ATEYDVFDXSKYOB-LLVKDONJSA-N COC([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O Chemical compound COC([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O ATEYDVFDXSKYOB-LLVKDONJSA-N 0.000 description 1
- QKNXAXGHTVYQJQ-GFCCVEGCSA-N COC([C@@H](C(C)C)NC(C1=CC(=CC(=C1)C)F)=O)=O Chemical compound COC([C@@H](C(C)C)NC(C1=CC(=CC(=C1)C)F)=O)=O QKNXAXGHTVYQJQ-GFCCVEGCSA-N 0.000 description 1
- YIKQJSUNKOCSEN-XMMPIXPASA-N COC=1C=C(C=CC1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C Chemical compound COC=1C=C(C=CC1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C YIKQJSUNKOCSEN-XMMPIXPASA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- DVTMIPFVPWWLJV-GNAFDRTKSA-N Cl.C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)N)=O)=O)C)=O Chemical compound Cl.C(C1=CC=CC=C1)OC(=O)N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)N)=O)=O)C)=O DVTMIPFVPWWLJV-GNAFDRTKSA-N 0.000 description 1
- YTSJPDKTTKPZBT-UHFFFAOYSA-N Cl.C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C)=O Chemical compound Cl.C(C1=CC=CC=C1)OC(C1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C)=O YTSJPDKTTKPZBT-UHFFFAOYSA-N 0.000 description 1
- JVLPHMQUKCMZNW-UHFFFAOYSA-N Cl.CN1C(N(C2(C1=O)CCNCC2)C2=CC=C(C(=O)O)C=C2)=O Chemical compound Cl.CN1C(N(C2(C1=O)CCNCC2)C2=CC=C(C(=O)O)C=C2)=O JVLPHMQUKCMZNW-UHFFFAOYSA-N 0.000 description 1
- WSFHNQHIUBJNQS-UHFFFAOYSA-N Cl.CN1C(N(C2(C1=O)CCNCC2)C2=CC=NC=C2)=O Chemical compound Cl.CN1C(N(C2(C1=O)CCNCC2)C2=CC=NC=C2)=O WSFHNQHIUBJNQS-UHFFFAOYSA-N 0.000 description 1
- RCBFIMHUYSXGFW-UHFFFAOYSA-N Cl.CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C(=O)N)C=C2 Chemical compound Cl.CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C(=O)N)C=C2 RCBFIMHUYSXGFW-UHFFFAOYSA-N 0.000 description 1
- ARPPGVQFALGDFM-UHFFFAOYSA-N Cl.CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C=C2)NC(C)=O Chemical compound Cl.CN1CN(C2(C1=O)CCNCC2)C2=CC=C(C=C2)NC(C)=O ARPPGVQFALGDFM-UHFFFAOYSA-N 0.000 description 1
- JRJPEHCWBIWZLG-UHFFFAOYSA-N Cl.COC(C1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)CCN(C)C)=O)=O Chemical compound Cl.COC(C1=CC=C(C=C1)N1C(N(C(C12CCNCC2)=O)CCN(C)C)=O)=O JRJPEHCWBIWZLG-UHFFFAOYSA-N 0.000 description 1
- KDPJSZWBEYYGGM-UHFFFAOYSA-N Cl.ClC=1C=C(C=CC1)N1CN(C(C12CCNCC2)=O)C Chemical compound Cl.ClC=1C=C(C=CC1)N1CN(C(C12CCNCC2)=O)C KDPJSZWBEYYGGM-UHFFFAOYSA-N 0.000 description 1
- PYFYPWVBEJICJJ-UHFFFAOYSA-N Cl.N=1NN=NC1C1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C Chemical compound Cl.N=1NN=NC1C1=CC=C(C=C1)N1CN(C(C12CCNCC2)=O)C PYFYPWVBEJICJJ-UHFFFAOYSA-N 0.000 description 1
- HEQMBSJYJNODGD-XFULWGLBSA-N Cl.N[C@@H](C(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1)C(C)C Chemical compound Cl.N[C@@H](C(=O)N1CCC2(C(N(C(N2C2=CC=CC=C2)=O)C)=O)CC1)C(C)C HEQMBSJYJNODGD-XFULWGLBSA-N 0.000 description 1
- YJSVSYAAIWLGOX-KUARMEPBSA-N Cl.N[C@@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)[C@H](C)OC Chemical compound Cl.N[C@@H](C(=O)N1CCC2(C(N(CN2C2=CC=CC=C2)C)=O)CC1)[C@H](C)OC YJSVSYAAIWLGOX-KUARMEPBSA-N 0.000 description 1
- VLNHDIUXVAENAZ-OAQYLSRUSA-N ClC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)Cl Chemical compound ClC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)Cl VLNHDIUXVAENAZ-OAQYLSRUSA-N 0.000 description 1
- CEGYCUYQYZXRGH-HSZRJFAPSA-N ClC1=C(C=CC=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C Chemical compound ClC1=C(C=CC=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=CC(=CC=C2)C)=O)=O)=O)C CEGYCUYQYZXRGH-HSZRJFAPSA-N 0.000 description 1
- YRCRZSGBPWHVRA-JOCHJYFZSA-N ClC1=CC=C(CN2C(N(C(C23CCN(CC3)C([C@@H](C(C)C)NC(C3=C(C=CC(=C3)C(F)(F)F)F)=O)=O)=O)C)=O)C=C1 Chemical compound ClC1=CC=C(CN2C(N(C(C23CCN(CC3)C([C@@H](C(C)C)NC(C3=C(C=CC(=C3)C(F)(F)F)F)=O)=O)=O)C)=O)C=C1 YRCRZSGBPWHVRA-JOCHJYFZSA-N 0.000 description 1
- SIJYLVCLFNCHSA-OAQYLSRUSA-N ClC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C1)Cl Chemical compound ClC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C1)Cl SIJYLVCLFNCHSA-OAQYLSRUSA-N 0.000 description 1
- PUDOGKJIUDKIDW-OAQYLSRUSA-N ClC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC1Cl Chemical compound ClC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC1Cl PUDOGKJIUDKIDW-OAQYLSRUSA-N 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 description 1
- 229930182831 D-valine Natural products 0.000 description 1
- 101001098814 Dictyostelium discoideum 3',5'-cyclic-nucleotide phosphodiesterase regA Proteins 0.000 description 1
- NICOGKFOAIXLOQ-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)C(F)(F)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)C(F)(F)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F NICOGKFOAIXLOQ-OAQYLSRUSA-N 0.000 description 1
- HUVDKCPZKDJIRU-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)F)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F HUVDKCPZKDJIRU-OAQYLSRUSA-N 0.000 description 1
- JPKGBNHMWSHGPJ-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=C(C=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F JPKGBNHMWSHGPJ-JOCHJYFZSA-N 0.000 description 1
- TXPSXZIHPCEXFF-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F TXPSXZIHPCEXFF-OAQYLSRUSA-N 0.000 description 1
- QARWOGZYCQXGSQ-OAQYLSRUSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CN(C(C=C3)=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CN(C(C=C3)=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F QARWOGZYCQXGSQ-OAQYLSRUSA-N 0.000 description 1
- CJYDPDOXVLTDPZ-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=C4C=NN(C4=CC3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C=3C=C4C=NN(C4=CC3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F CJYDPDOXVLTDPZ-HSZRJFAPSA-N 0.000 description 1
- IMHHPEPUHQCPDX-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC(=CC=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC(=CC=C3)S(=O)(=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F IMHHPEPUHQCPDX-HSZRJFAPSA-N 0.000 description 1
- NAYGITXNXIHYHT-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC=4N(C=C3)C=CN=4)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CC=4N(C=C3)C=CN=4)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F NAYGITXNXIHYHT-HSZRJFAPSA-N 0.000 description 1
- NSNMFIWOXTXBIJ-JOCHJYFZSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CN(C(C=C3)=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC3=CN(C(C=C3)=O)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F NSNMFIWOXTXBIJ-JOCHJYFZSA-N 0.000 description 1
- NIPMGVAATRVWNE-XMMPIXPASA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=CC4=C(N=C(O4)C)C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=CC4=C(N=C(O4)C)C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F NIPMGVAATRVWNE-XMMPIXPASA-N 0.000 description 1
- ZRWJXKPVRKZSMD-HXUWFJFHSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=NN(C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3CC=3C=NN(C3)C)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F ZRWJXKPVRKZSMD-HXUWFJFHSA-N 0.000 description 1
- XSPPBSRUOZLLIM-FDDCHVKYSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3[C@@H](C)C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3[C@@H](C)C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F XSPPBSRUOZLLIM-FDDCHVKYSA-N 0.000 description 1
- UGGCRELAIDTUIN-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC(=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC(=C(C(=O)O)C=C3)C)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F UGGCRELAIDTUIN-HSZRJFAPSA-N 0.000 description 1
- SYMAHTMNWKYCSK-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC(=C(C(=O)O)C=C3)OC)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC(=C(C(=O)O)C=C3)OC)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F SYMAHTMNWKYCSK-HSZRJFAPSA-N 0.000 description 1
- GMXMCKXBUPLWRK-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C=C(C=C1)OC Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C(=O)O)C=C3)C)=O)CC2)C(C)C)C=C(C=C1)OC GMXMCKXBUPLWRK-HSZRJFAPSA-N 0.000 description 1
- QUJPPYISLDYWBK-RUZDIDTESA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)NC3COC3)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=C(C=C3)NC3COC3)C)=O)CC2)C(C)C)C=C(C=C1)C(F)(F)F QUJPPYISLDYWBK-RUZDIDTESA-N 0.000 description 1
- SKIMFNPYHUYVFV-HSZRJFAPSA-N FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C=3C=C(C=CC3)B(O)O)C)=O)CC2)C(C)C)C=CC=C1C Chemical compound FC1=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C=3C=C(C=CC3)B(O)O)C)=O)CC2)C(C)C)C=CC=C1C SKIMFNPYHUYVFV-HSZRJFAPSA-N 0.000 description 1
- QBMVYVJWNKXVLA-OAQYLSRUSA-N FC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC1 Chemical compound FC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(C(N3C3=CC=CC=C3)=O)C)=O)CC2)C(C)C)C=CC1 QBMVYVJWNKXVLA-OAQYLSRUSA-N 0.000 description 1
- LRPMEFKJMWMCGK-HSZRJFAPSA-N FC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=C(C1)C Chemical compound FC=1C=C(C(=O)N[C@@H](C(=O)N2CCC3(C(N(CN3C3=CC=CC=C3)C)=O)CC2)C(C)C)C=C(C1)C LRPMEFKJMWMCGK-HSZRJFAPSA-N 0.000 description 1
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000575946 Ione Species 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- LCJOQRSTIMFYCP-HSZRJFAPSA-N N1N=C(N=C1)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C Chemical compound N1N=C(N=C1)C1=CC=C(C=C1)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C LCJOQRSTIMFYCP-HSZRJFAPSA-N 0.000 description 1
- CDSKRHGFXHZEQL-JOCHJYFZSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C)=O CDSKRHGFXHZEQL-JOCHJYFZSA-N 0.000 description 1
- TWKSGEPTRAKZPK-OAQYLSRUSA-N N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=NC=CC=C2)=O)=O)=O)C)=O Chemical compound N1N=CC2=CC(=CC=C12)N1C(N(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=NC=CC=C2)=O)=O)=O)C)=O TWKSGEPTRAKZPK-OAQYLSRUSA-N 0.000 description 1
- HTLMYSKXWHNOPG-HSZRJFAPSA-N N1N=CC2=CC(=CC=C12)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C Chemical compound N1N=CC2=CC(=CC=C12)N1CN(C(C12CCN(CC2)C([C@@H](C(C)C)NC(C2=C(C=CC(=C2)C(F)(F)F)F)=O)=O)=O)C HTLMYSKXWHNOPG-HSZRJFAPSA-N 0.000 description 1
- 101150071357 NPP2 gene Proteins 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- KWOKRNLQLCBPBQ-JOCHJYFZSA-N O1C=NC2=C1C=CC(=C2)N2C(N(C(C21CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O Chemical compound O1C=NC2=C1C=CC(=C2)N2C(N(C(C21CCN(CC1)C([C@@H](C(C)C)NC(C1=C(C=CC(=C1)C(F)(F)F)F)=O)=O)=O)C)=O KWOKRNLQLCBPBQ-JOCHJYFZSA-N 0.000 description 1
- UGHRRXXJNLINJN-VQIWEWKSSA-N OC(=O)C(F)(F)F.CC(C)[C@@H](NC(=O)C1=C(F)C=CC(=C1)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(OCC2CNC2)C=C1 Chemical compound OC(=O)C(F)(F)F.CC(C)[C@@H](NC(=O)C1=C(F)C=CC(=C1)C(F)(F)F)C(=O)N1CCC2(CC1)N(C(=O)N(C)C2=O)C1=CC=C(OCC2CNC2)C=C1 UGHRRXXJNLINJN-VQIWEWKSSA-N 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 101100080097 Phytophthora capsici NLP2 gene Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- VZOVOHRDLOYBJX-UHFFFAOYSA-N benzyl 4-oxopiperidine-1-carboxylate Chemical compound C1CC(=O)CCN1C(=O)OCC1=CC=CC=C1 VZOVOHRDLOYBJX-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- DGLFSNZWRYADFC-UHFFFAOYSA-N chembl2334586 Chemical compound C1CCC2=CN=C(N)N=C2C2=C1NC1=CC=C(C#CC(C)(O)C)C=C12 DGLFSNZWRYADFC-UHFFFAOYSA-N 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- HXSNGAHNYZBZTH-UHFFFAOYSA-N cyclopropylmethanamine;hydrochloride Chemical compound Cl.NCC1CC1 HXSNGAHNYZBZTH-UHFFFAOYSA-N 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 1
- YJIRDHXJRYYJHD-UHFFFAOYSA-N decane-2,4-dione;hydrochloride Chemical compound Cl.CCCCCCC(=O)CC(C)=O YJIRDHXJRYYJHD-UHFFFAOYSA-N 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 description 1
- HDRXZJPWHTXQRI-BHDTVMLSSA-N diltiazem hydrochloride Chemical compound [Cl-].C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CC[NH+](C)C)C2=CC=CC=C2S1 HDRXZJPWHTXQRI-BHDTVMLSSA-N 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000010363 gene targeting Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 125000003564 m-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(C#N)=C1[H])C([H])([H])* 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- KUGLDBMQKZTXPW-NUBCRITNSA-N methyl (2r)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](N)C(C)C KUGLDBMQKZTXPW-NUBCRITNSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 230000001617 migratory effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- HWYHDWGGACRVEH-UHFFFAOYSA-N n-methyl-n-(4-pyrrolidin-1-ylbut-2-ynyl)acetamide Chemical compound CC(=O)N(C)CC#CCN1CCCC1 HWYHDWGGACRVEH-UHFFFAOYSA-N 0.000 description 1
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 125000003544 oxime group Chemical group 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229940081066 picolinic acid Drugs 0.000 description 1
- FSDNTQSJGHSJBG-UHFFFAOYSA-N piperidine-4-carbonitrile Chemical compound N#CC1CCNCC1 FSDNTQSJGHSJBG-UHFFFAOYSA-N 0.000 description 1
- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002206 pro-fibrotic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- ZBTCTIDRZAHCCK-UHFFFAOYSA-N tert-butyl 3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC21C(=O)N(C)CN2C1=CC=CC=C1 ZBTCTIDRZAHCCK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Definitions
- ATX Autotaxin
- ATX Pyrophosphatase/Phosphodiesterase 2 (ENPP-2 or NPP2).
- ENPP-2 or NPP2 Pyrophosphatase/Phosphodiesterase 2
- LPC Lysophosphatidylcholine
- LPA Lysophosphatidic Acid
- LPA Low-power plasma phosphatidylcholine
- IPF Idiopathic Pulmonary Fibrosis
- thrombosis thrombosis
- cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or activation of ATX.
- Fibrotic diseases are chronic, debilitating and often lethal pathologies driven by a dysregulated response to tissue or organ injury. Fibrosis can develop in the liver, kidney, lung, dermis, vasculature, gut and other sites. Fibrosis develops due to action of pathways including growth factors, cytokines, integrin and lipids.
- ATX, LPA, and LPA Receptor (LPAR) pathways have been implicated in fibrotic disease.
- profiling studies show increased levels of ATX, LPA and LPARs in various rodent models of fibrosis and in human patient fluids and biopsy tissue.
- LPA can induce proliferative, survival, and chemotactic responses in transformed cell lines, indicating that LPA may exert pro-inflammatory and pro- fibrotic responses in cells known to be critical in fibrotic disease, including: fibroblasts, smooth muscle cells, macrophages, epithelial and endothelial cells, and leukocytes.
- Gene-targeted mouse models have implicated LPARs in fibrosis pathogenesis.
- Inhibitors of LPARs indicate that antagonism of receptors within this pathway blocked or reversed fibrosis in the lung, liver, kidney and skin in rodents.
- Cell type-specific gene targeting studies have showed that ATX plays a role in the development of lung fibrosis and inflammatory arthritis.
- ATX and LPA have also been implicated in tumor progression and metastasis.
- ATX may be responsible for increased LPA levels in ascites and plasma of ovarian cancer patients since ATX converts LPC to LPA.
- Increased levels of LPA, altered receptor expression and altered responses to LPA may contribute to initiation, progression or outcome of ovarian cancer.
- LPA has also been linked to prostate, breast, melanoma, head and neck, bowel, brain and thyroid cancers.
- LPA has been shown to promote tumor cell survival, proliferation, invasion and migration into neighboring tissues, which can result in the formation of metastases. Additionally, LPA promotes cytoskeletal remodeling that may enhance migratory and invasive properties of cells, which may contribute to cancer metastasis.
- Transcriptome analyses of more than 350 normal tissues and more than 1700 malignant tissues demonstrate that ATX is expressed in a variety of carcinomas and sarcomas, underscoring the potential contribution of LPA to metastatic disease.
- LPA levels when treating patients with diseases, such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus it is desirable to lower LPA levels. This can be accomplished through inhibition of enzymes involved in LPA biosynthesis, such as ATX.
- ATX is expressed in tumors and affects tumor cell proliferation and invasion into neighboring tissues both of which can lead to the formation of metastases
- ATX is a target for anti-tumor therapy.
- ATX taken with other anti-angiogenetic factors, brings about blood vessel formation.
- Angiogenesis supplies tumors with nutrients during tumor growth. Therefore, inhibition of angiogenesis is a target for anti-tumor therapy, leading to starvation of a tumor.
- ATX has also been implicated in nerve injury-induced neuropathic pain.
- LPA biosynthesis, through ATX, is the source of LPA for LPA1 receptor-mediated neuropathic pain. Therefore, targeted inhibition of ATX-mediated LPA biosynthesis may represent a novel treatment to prevent nerve injury- induced neuropathic pain.
- ATX inhibitors having the potential to reach the clinic and obtain regulatory approval for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or the activation of ATX.
- physiological and/or pathophysiological conditions such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or the activation of ATX.
- the present invention includes certain substituted compounds described herein, their salts, preparations thereof, pharmaceutical compositions and formulations thereof, and methods of treating disease such as cancers therewith.
- the present invention includes compounds of Formula I and pharmaceutically acceptable salts thereof:
- X 2 is selected from C 1-2a
- kyl , C 0, NR 3 or O
- R 1 , R 7 , R 2a , R 4 , R 10 and R 1 1 are each independently optionally substituted; and
- m and n are each independently selected from 0, 1 or 2. Any of the above can be further substituted.
- Compounds of Formula I inhibit ATX.
- compounds of the present invention are inhibitors of ATX. In some embodiments, compounds of the present invention are selective inhibitors of ATX.
- the present invention includes a method for the treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of Formula I that binds to and inhibits ATX providing a reduction in LPA levels.
- Embodiments of the present invention include the compounds herein, pharmaceutically acceptable salts thereof, any physical forms thereof including solvates and hydrates, preparation of the compounds, intermediates, and pharmaceutical compositions and formulations thereof.
- the present invention concerns compounds and salts thereof of Formula I, as shown below and defined herein.
- n are each independently selected from 0, 1 or 2;
- R 1 is selected from Co-i 2 alkyl-, C 3 . 12 cycloalkyl-C 0 -i2alkyl-, C3_i2heterocycloalkyl-C 0 . 12 alkyl- aryl- C 0 -i 2 alkyl-, aryl-C ⁇ cycloalkyl- aryl-C 3 .i 2 heterocycloalkyl- heteroaryl-C 0 -i 2 alkyl- heteroaryl-C 3 _ i 2 cycloalkyl- or heteroaryl-C 3 _i 2 heterocycloalkyl- any of which is optionally substituted with one or more independent G 1 substituents;
- R 2 is selected from Co-i 2 alkyl- C 3 . 12 cycloalkyl-C 0 -i 2 alkyl-, C 3 -i 2 heterocycloalkyl-C 0 -i 2 alkyl- aryl- C 0 -i 2 alkyl- aryl-C 3 .i 2 cycloalkyl- aryl-C 3 _ 12 heterocycloalkyl- heteroaryl-C 0 -i 2 alkyl- heteroaryl-C 3 _ , 2 cycloalkyl- or heteroaryl-C 3 _ 12 heterocycloalkyl- any of which is optionally substituted with one or more independent G 2 substituents;
- R 2a is selected from Co. 12 alkyi- C 3 . 12 cycloalkyl-Co-i2alkyl-, Ci ⁇ eterocycloalkyl-Co. ⁇ alkyl- aryl-
- R 2 and R a are each independently a linear structure, or, R 2 and R 2a are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m1 ;
- R 3 is selected from C 0 -i 2 alkyi-, C 3 . 12 cycloalkyl-Co-i 2 alkyl- C 3 . t2 heterocycloalkyl-C 0 _ 12 alkyl-, aryl-
- R 4 is selected from C 0 -i 2 alkyl- C 3 - 12 cycloalkyl-Co_ 12 alkyl- C 3 . 12 heterocycloalkyl-C 0 . 12 alkyl-, aryl— C 0 -i 2 alkyl-, aryl-C 3 . 12 cycloalkyl-, aryl-C 3 . 12 heterocycloalkyl- heteroaryl-C 0 -i 2 alkyl-, heteroaryl-C 3 _ 2cycloalkyl- heteroaryl-C 3 . 2 heterocycloalkyl-, or pyridine-N-oxide, any of which is optionally substituted with one or more independent G 4 substituents;
- G 1 , G 2 , G a , G 3 , and G 4 are each independently selected from one or more of H, D, halo, -CN, -
- Q 1 is selected from H, ⁇ , halo, -CN , -CD 3l -OCD 3 , -0x0-, -CF 3 , -OCF 3l -OCHF 2 , -N0 2 , -
- Q 2 is selected from one or more of H, D, halo, -CN, -0x0-, -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -
- R 5 , R e , R 10 , R 11 , R 12 , R 13 R 14 , R 15 , and R 16 are each independently selected from one or more of H, d-salkyl-, C 3 _ 8 cycloalkyl-Co_ 6 alkyl- C 3 . 8 heterocycloalkyl-C 0 - 6 alkyl-, aryl-Co. e alkyl-, aryl-C 3 _ acycloalkyl-, aryl-C 3 . 8 heterocycloalkyl-, heteroaryl-Ci. 6 alkyl-, heteroaryl-C 3 .
- B cycloalkyl- or heteroaryl- C 3 . 8 heterocycloalkyl-, any of which may be optionally substituted;
- R 17 , R 18 , R 9 , R 20 , R 21 , R 27 R 28 , R 29 , and R 30 are each independently selected from H, C 1-6 alkyl-
- R 6 and -NR 12 R 13 are each independently a linear structure, or, R 6 and R 6 , or R 12 and R 13 , respectively, are taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m2 ;
- -CR 0 R 11 and -CR 14 R 15 are each independently a linear structure, or, R 0 and R 11 , or R 14 and R 15 respectively, are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms selected from O, N, or S(0) m3 ;
- R 19 R 20 is a linear structure, or, R 19 and R 20 are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m4 ;
- -NR 17 R 18 is a linear structure, or, R 17 and R 18 are taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m5 ;
- -CR 29 R 30 is a linear structure, or, R 29 and R 30 are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m6 ;
- -NR 27 R 28 is a linear structure, or, R 27 and R 28 are taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m7 ;
- nl , m2, m3, m4, m5, m6, m7, n1 , n2, n3, n4, n5 and n6 are each independently selected from 0, 1 or 2;
- R 1 is selected from one of C 3 . 8 cycloalkyl-Co-_alkyl-, C 3 - 8 heterocycloalkyl-C 0 - 8 alkyl-, aryl-C 0 . s alky I— , or heteroaryl-C 0 - 8 alkyl-;
- G is selected from one of H, halo, -CN, -oxo- -CF 3 , -OCF 3 , -OCHF 2 , -NR 5 R e , -N0 2 , -OC 0 _ a alkyl, -S(0) n1 R 12 -B(OH) 2 , -C 0 . 8 alkyl, -C 2 _ a alkenyl, -C 2 - 8 alkynyl, C 3 _ 8 cycloalkyl-C 0 . 8 alkyl-,C 3 _ sheterocycloalkyl-Co-aalkyl-, aryl-Co- 8 alkyl- or heteroaryl-C 0 -salkyl- In some embodiments of Formula I:
- G is selected from 0 to 3 of H, halo, -CN, -oxo- -CF 3 , -OCF 3 , -OCHF 2l -NR 5 R 6 , -N0 2 , -OC 0 . 8 alkyl, -S(0) nl R 12 -B(OH) 2 , -C 0 . 8 aikyl, -C 2 _ 8 alkenyl, -C 2 . 8 alkynyl, C 3 _ 8 cycloalkyl-Co- S alkyl-,C 3 .
- R 2 is selected from Co- 8 alkyl- C 3 _ s cycloalkyl-Co- 8 alkyl- or C 3 _ 8 fieterocycloalkyl-Co-8alkyl-;
- R 2a is C 0 - 8 alkyl-
- G 2 is selected from one or more of H, halo, -CN -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -OCHF 2l or -OC 0 . a alkyl;
- R 2 and R 2a are each independently a linear structure, or, R 2 and R 2a are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, or N.
- G 2 is selected from 0 to 3 of H, halo, -CN, -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -OCHF 2 , or -OC 0 . 8 alkyl.
- R 3 is selected from C 0 - 8 alkyl-, C 3 _ 8 cycloalkyl-C 0 - 8 alkyl-, or C 3 _ 8 heterocycloalkyl-Co- 8 alkyl-;
- G 3 is selected from one or more of H, D, halo, -CN, -CD 3 , -OCD 3 , -oxo-, -CF 3 , -OCF 3 , - OCHF 2 ,— R 5 R 6 , -Co- 8 alkyl, -C 2 . 8 alkenyl, -C 2 _ 8 alkynyl, -OC 0 . 8 alkyl, -S(0) n1 R 12 , -C(0)R 12 , -C(0)NR 1 R 13 , or -C(0)OR 1
- G 3 is selected from 0 to 3 of H, D, halo, -CN, -CD 3 , -OCD 3 , -oxo-, -CF 3 , -OCF 3 , -OCHF 2 , - NR 5 R 6 , -C 0 . 8 alkyl, -C 2 _ 8 alkenyl, -C 2 . 8 alkynyl, -OC 0 - 8 alkyl, -S(0) n1 R 12 , -C(0)R 12 , -C(0)NR 12 R 13 or - C(0)OR 12
- R 4 is selected from Co-aalkyl-, C 3 . 8 cycloalkyl-C 3 _ 8 alkyl-, C 3 . 8 heterocycloalkyl-C 0 _ 8 alkyl-, aryl-Co- s alky I— , heteroaryl-C D . s alkyl-, heteroaryl-C 3 . 8 cycloalkyl- heteroaryl-C 3 . 8 heterocycloalkyl- or pyridine-N- oxide;
- G 4 is selected from one or more of H, D, halo, -CN, -CD 3 , -OCD 3 , -oxo-, -CF 3 , -OCF 3 , - OCHF 2 , -NR 5 R 5 -N0 2 , -B(OH) 2 , -CONR 12 OH, -C 0 .
- alkyl C 3 _ 8 cycloalkyl-C M alkyl- C 3 - 8 heterocycloalkyl- Co ⁇ alkyl- aryl-Co-ealkyl- heteroaryl-C 0 - 8 alkyl- -OC 0 .
- G 4 is selected from 0 to 3 of H, D, halo, -CN, -CD 3 , -OCD 3 , -oxo- -CF 3 , -OCF 3 , -OCHF 2 , -
- Q 1 is selected from H, D, halo, -CN, -CD 3 , -OCD 3 , -oxo-, -CF 3 , -OCF 3 , -OCHF 2 , NR"R '°, C 0 _ 8 alkyl- aryi— C 0 . 8 alkyl-, heteroaryl-C Q . 8 alkyl-, C 3 . 8 cycloalkyl-Co. 8 alkyl-, C 3 _ 8 heterocycloalkyl-Co- 8 alkyl-, aryl-C 0 .
- R 1 is selected from one of C 3 . 6 cycloalkyl-Co-salkyl- C 3 . 6 heterocycloalkyl-C D . 6 alkyl-, aryl-C 0 . 6 alkyl— , or heteroaryl-C 0 - 6 alkyl-;
- G 1 is selected from one of H, halo, -CN, -0x0-, -CF 3 , -OCF 3 , -OCHF 2 , -NR 5 R 6 , -N0 2 , -OC 0 . 6 alkyl, -S(0) n1 R 12 , -B(OH) 2l -C 0 - 6 alkyl, -C 2 _ 6 alkenyl, -C 2 . s alkynyl, C 3 . e cycloalkyl-C 0 . 6 alkyl-,C 3 .
- G 1 is selected from 0 to 2 of H, halo, -CN, -0x0-, -CF 3 , -OCF 3 , -OCHF 2 , -NR 5 R B , -N0 2 , -OC 0 . s alkyl, -S(0) n1 R 12 , -B(OH) 2 , -C 0 _ 6 alkyl, -C 2 _ 6 alkenyl, -C 2 protagonist 6 alkynyl, C 3 - 6 cycloalky!-C 0 - 6 alkyl-,C 3 _
- R 2 is selected from C 0 _ 6 alkyl— , C 3 _ 6 cycloalkyl-Co. s alkyl- or C 3 _ 6 heterocycloalkyl-C 0 -salkyl-;
- R 2a is Co- 6 alkyl-
- G 2 is selected from one or more of H, halo, -CN, -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -OCHF 2 , or -OC 0 . salkyl;
- R 2 and R 2a are each independently a linear structure, or, R 2 and R 2a are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, or N.
- R 2 and R 2a are each independently a linear structure, or, R 2 and R 2a are taken together with the carbon atom to which they are attached to form a 4-6 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, or N.
- G 2 is selected from 0 to 2 of H, halo, -CN, -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -OCHF 2 , or -OCo- 6 alkyl.
- R 3 is selected from C 0 -6alkyl- C 3 _ 5 cycloalkyl-C a . 6 alkyl-, or C 3 .gheterocycloalkyl-C 0 -6alkyl-;
- G 3 is selected from one or more of H, D, halo, -CN, -CD 3 , -OCD 3 , -0x0-, -CF 3 , -OCF3, - OCHF 2 , -NR R 6 , -C 0 . 6 alkyl, -C 2 . 5 alkenyl, -C 2 _ 5 alkynyl, -OC 0 - 6 alkyl, -S(0) n1 R 12 , -C(0)R 12 , -C(0)NR 12 R 13 , or -C(0)OR 12
- G 3 is selected from 0 to 2 of H, D, halo, -CN, -CD 3 , -OCD 3 , -0x0-, -CF 3 , -OCF 3 , -OCHF 2 , - NR 5 R 6 , -C 0 . e alkyi, -C 2 . e alkenyl, -C 2 . 6 alkynyl, -OC 0 _ 6 alkyl, -S(0) n1 R 12 , -C(0)R 12 , -C(0)NR 1 R 13 , or - C(0)OR 12
- R 4 is selected from C 0 - 6 alkyl- C 3 - 6 cycloalkyl-C 0 -ealkyl-, C 3 . 6 heterocycloalkyl-C 0 _ 6 alkyl-, aryl-C 0 . 5 alkyl— , heteroaryl-C 0 - B alkyl- heteroaryl-C 3 . B cycloalkyl-, heteroaryl-C 3 . e heterocycloalkyl- or pyridine-N- oxide;
- G 4 is selected from one or more of H, D, halo, -CN, -CD 3 , -0CD 3l -oxo- -CF 3 , -OCF 3 , - OCHF 2 , -NR 5 R 6 , -N0 2 , -B(OH) 2 , -CONR ,2 OH, -C 0 . 6 alkyl, C 3 _ e cycloalkyl-C o s atkyl- C 3 6 heteracycloalkyl- Co_ 6 alkyk, aryl-C 0 .
- G 4 is selected from 0 to 2 of H, ⁇ , halo, -CN, -CD 3 , -OCD 3 , -oxo-, -CF 3 , -OCF 3l -OCHF 2 , - NR 5 R S , -N0 2 , -B(OH) 2l -CONR 12 OH, -Co. 6 alkyl, C 3 . 6 cycloalkyl-Co. 6 alkyl-, C 3 . 6 heterocycloalkyl-Co- 6 alkyl- , aryl-C D . 6 alkyl- heteroaryl-Co. 6 alkyl- -OC 0 .
- Q is selected from H, ⁇ , halo, -CN, -CD 3 , -OCD 3 , -oxo- -CF 3 , -0CF 3 , -OCHF 2 , NR 17 R 16 , C 0 . s alkyl- aryl-Co-ealkyl-, heteroaryl-C 0 _ 6 alkyl-, C 3 . s cycloalkyl-C u . e alkyl-, C 3 . 6 heterocycloalkyl-C 0 -6alkyl-, aryl-C 0 . 6 cycloalkyl-, heteroaryl-C 3 . s cycloalkyl-, C 3 .
- R 2 is selected from methyl following groups:
- R a is selected H, methyl, ethyl, propyl, isopropyl; or
- R 2 and R a are taken together with the carbon atom to which they are attached to form one of the following groups:
- R 1 is selected from one of CgCycloalkyl-Co-ealkyl- C 6 heterocycloalkyl-C M alkyl- 6-membered- aryl-C 0 - 6 alkyl- or 6-membered-heteroaryl-C 0 _ 6 alkyl-,
- -NR 5 R 6 and -NR 12 R 13 are each independently a linear structure, or, R 5 and R 6 , or R 12 and R 3 , respectively, are taken together with the nitrogen atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from 0, N, or S(0) m2 ;
- R 11 and -CR 1 R 16 are each independently a linear structure, or, R 1C and R 11 , or R and R 15 respectively, are taken together with the carbon atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms selected from O, N, or S(0) m3 ;
- R 19 R 20 is a linear structure, or, R 19 and R 20 are taken together with the carbon atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m4 ;
- -NR 17 R 18 is a linear structure, or, R 17 and R 18 are taken together with the nitrogen atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) mS ;
- -CR 29 R 3D is a linear structure, or, R 29 and R 30 are taken together with the carbon atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m6 ;
- -NR 27 R 28 is a linear structure, or, R 27 and R 28 are taken together with the nitrogen atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) rn7 ;
- m2, m3, m4, m5, rr>6, and m7 are each independently selected from 0, 1 or 2.
- compounds of the present invention are a subgenus of Formula I, having the Formula la:
- R 2a is hydrogen
- R 2 is C _ 2 alkyl-, any of which is optionally substituted with one or more independent G 2 substituents (e.g., methyl, ethyl, iso-propyl, sec-butyl, cyclopropyl, cyclobutyl, cyc!opentyl, or cyclohexyl).
- R 1 is aryl or heteroaryl, any of which is optionally substituted with one or more independent G 1 substituents. In other embodiments, of Formula la, R 1 is aryl.
- the 4-position of said aryl is H, and wherein the 2, 3, 5 and 6 positions of said aryl are optionally substituted by one or more G 1 substituents.
- said 2, 3, 5, and 6 positions are optionally substituted with halo (e.g. , fluoro, chloro, bromo), C 1-6 alkyl (e.g., methyl, ethyl, CF 3 ), Ci_ 6 heteroalkyl (e.g., methoxy, trifluoromethoxy), or C 3 . 8 cycloalkyl (e.g., cyclopropyl).
- R is 3-methyl-phenyl, 3-methyl-4-fluoro-phenyl, 2-fluoro-5-ethyl- phenyl, 2-fluoro-5-trifluoromethyl-phenyl, 3-fluoro-5-methyl-phenyl, 2-fluoro-5-cyclopropyl-phenyl, 2- fluoro-5-chloro-phenyl, 3, 5-dichloro-phenyl, 2-fluoro-5-methyl-phenyl, 3-chloro-5-trifluoromethyl-phenyl, 2- fluoro-5-trifluromethoxy-phenyl, 2-fluoro-5-difluoromethoxy-phenyl, 3-fluoro-5-ethyl-phenyl, 3-cyclopropyl, 3-ethyl-phenyl, 2-fluoro-3-methyl-phenyl, or 2-fluoro-5-methoxy-phenyl.
- R 4 is C 1 12 alkyl (e.g., iso-butyl), C 3 8 cycloalkyl (e.g. , cyclopentyl or cyclohexyl), aryl (e.g., phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl, 4-cyano- phenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-chloro-phenyl, 3-bromo-phenyl, 4-deutero-phenyl, 4-trifluoromethyl-phenyl, 4-carboxy-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl- phenyl, 3,4-dichloro-phenyl, 4-ethoxy-phenyl, 4-trideuteromethoxy-phenyl, 4-carboxymethyl-phenyl, 4- (o
- compounds of the present invention are a subgenus of Formula I , having the Formula Ih:
- the 4-position of the phenyl ring in Formula Ih is H, and wherein the 2, 3, 5 and 6 positions of the phenyl ring in Formula Ih are optionally substituted by one or more G 1 substituents.
- R 3 is selected from methyl, ethyl, propyl, isopropyl, -(CH 2 )i_ 3 -cyclopropyl, C3.8cycloalk.yl, -(CH 2 )i. 3 CN, -(CH 2 )i- 3 C(0)OH , or -(CH 2 ) 1 . 3 S(0) 2 Me.
- X 2 is selected from Ci_ 2a ik y i, NR 3 or O;
- R 10 and R 11 are each independently equal to H or C h alky!
- n are each equal to 1.
- the compounds of Formula I are inhibitors of ATX.
- the compound of Formula I is any one of the compounds described herein (e.g., any one of the compounds described in Examples 1 to 246)
- the present invention includes a pharmaceutical composition comprising the compound or salt of any one of the compounds of Formula I , formulated with or without one or more pharmaceutical carriers.
- the present invention includes a method for the treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus mediated at least in part by ATX comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of Formula I.
- the present invention includes a method for the treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of Formula I that binds to and inhibits ATX providing a reduction in LPA levels.
- the present invention includes a method of treating fibrosis, inflammation, cancer, angiogenesis, or pain in a mammal comprising administering a therapeutically effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
- the present invention includes a method of treating lung fibrosis, asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis, skin fibrosis, fibrosis of the gut, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, B cell lymphoma, T cell lymphoma, cancer pain, tumor metastasis, transplant organ rejection, scleroderma, ocular fibrosis, age related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenom, rheumatoid arthritis, osteoarthritis or neuropathic pain in a mammal comprising administering a therapeutically effective amount of a compound according Formula I
- COPD
- the present invention further includes administering to the mammal one or more additional therapeutically active agents selected from: corticosteroids, immunosuppressants, analgesics, anti-cancer agents, anti-inflammatories, non-steroidal anti-inflammatories, dual
- cyclooxygenase-1 and -2 inhibitors cyclooxygenase-2 selective inhibitors, TNFa blockers, kinase inhibitors, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, prostaglandin receptor antagonists, prostaglandin formation inhibitors,
- monoacylglycerol kinase inhibitors phospholipase A1 inhibitors, phospholipase A2 inhibitors, lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors, and LPA receptor antagonists.
- compounds are present as a material in substantially pure form.
- compounds are selected from any one of the Examples herein or a pharmaceutically acceptable salt thereof.
- variable definition above includes any subset thereof and the compounds of Formula I include any combination of such variables or variable subsets.
- the present invention includes the compounds and salts thereof, their physical forms, preparation of the compounds, useful intermediates, and pharmaceutical compositions and formulations thereof.
- the compounds of the present invention and the term "compound” in the claims include any pharmaceutically acceptable salts or solvates, and any amorphous or crystal forms, or tautomers, whether or not specifically recited in context.
- the present invention includes all isomers of the compounds.
- Compounds may have one or more asymmetric carbon atoms can exist as two or more stereoisomers.
- a compound of the invention contains an alkenyl or alkenylene group
- geometric cis/trans (or Z/E) isomers are possible.
- the compound contains, for example, a keto or oxime group or an aromatic moiety
- tautomeric isomerism ('tautomerism') can occur.
- a single compound may exhibit more than one type of isomerism.
- the present invention includes any stereoisomers, even if not specifically shown, individually as well as mixtures, geometric isomers, and pharmaceutically acceptable salts thereof. Where a compound or stereocenter is described or shown without definitive stereochemistry, it is to be taken to embrace all possible individual isomers, configurations, and mixtures thereof. Thus, a material sample containing a mixture of stereoisomers would be embraced by a recitation of either of the stereoisomers or a recitation without definitive stereochemistry. Also contemplated are any cis/trans isomers or tautomers of the compounds described
- the present invention includes all stereoisomers, geometric isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
- the compound of Formula I of the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
- R 1 , R 2 , R 2a , R 3 , R 4 , X 3 , m and n are as previously described for a compound of Formula I.
- a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula lb:
- R 1 , R 2 , R 2a , R 3 , R 4 , R 0 R 1 , m and n are as previously described for a compound of Formula I.
- R 1 , R 2 , R 2a X 1 - X 3 , G 4 , m and n are as previously described for a compound of Formula I and wherein E99 is equal to 0, 1 , 2, or 3.
- a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Id:
- R 1 , R 2 , R 2a , X 1 - X 3 , G 4 m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C h alky], O, N or S and wherein E99 is equal to 0, 1 , 2, or 3.
- R 1 , R 2 , R 2a R 3 , G 4 , m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0 - 2 alkyl, O, N or S and wherein E99 is equal to 0, 1 , 2, or 3.
- R 1 , R 2 , R 2a , R 3 R 1D , R 1 , G 4 , m and n are as previously described for a compound of Formula I , wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0 - 2 alkyl, O, N or S and wherein E99 is equal to 0, 1 , 2, or 3.
- R 2 , R 2a , R 3 , R 4 , X 3 , G , m and n are as previously described for a compound of Formula I.
- a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula li:
- R 2 , R 2a R 3 R 4 , R 10 , R 11 , G 1 , m and n are as previously described for a compound of Formula I.
- R 2 , R 2a , X 1 - X 3 , G 1 , G 4 , m and n are as previously described for a compound of Formula I and wherein E99 is equal to 0, 1 , 2, or 3.
- R 2 , R 2a , X 1 - X 3 , G 1 , G 4 m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and z'-Z 6 are each independently selected from one or more of C 0 . 2 alkyl, O, N or S and wherein E99 is equal to 0, 1 , 2, or 3.
- R 2 , R 2a , R 3 G 1 , G 4 , m and n are as previously described for a compound of Formula I, wherein Y -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0 . 2 alkyl, O, N or S and wherein E99 is equal to 0, 1 , 2, or 3.
- a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula In:
- R 2 , R 2a , R 3 R 10 , R 1 , G 1 , G 4 , m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0 . 2 alkyl, O, N or S and E99 is equal to 0, 1 , 2, or 3.
- R 2 , R 2a , R 3 R 4 , X 3 , G 1 , m and n are as previously described for a compound of Formula I.
- the present invention includes the compounds, intermediates, examples and synthetic methods described herein.
- Compounds of Formula I are prepared according to reaction schemes described herein. Unless otherwise indicated, the substituents in the schemes are defined as above.
- Compounds of the present invention include the intermediates, examples, and synthetic methods described herein.
- the compounds of Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art.
- the starting materials used herein are commercially available or may be prepared by routine methods known in the art [such as those methods disclosed in standard reference books such as the Compendium of Organic Synthetic Methods, Vol. I-VI (Wiley-lnterscience); or the Comprehensive Organic Transformations, by R. C. Larock (Wiley-lnterscience)].
- Preferred methods include, but are not limited to, those described below.
- any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 , and T. W. Greene and P. G. . Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.
- conventional protecting groups such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 , and T. W. Greene and P. G. . Wuts, Protective Groups in Organic Chemistry, John Wiley &
- a compound of Formula II and Ma were reacted under suitable amide coupling conditions.
- HATU in the presence of diisopropylethyl amine (DIPEA) can be used.
- DIPEA diisopropylethyl amine
- Suitable solvents for use in the above process included, but were not limited to, ethers such as THF, glyme, and the like; DMF; DMSO; MeCN; halogenated solvents such as chloroform or DC .
- mixtures of these solvents were used, however the preferred solvents were DCM and DMF.
- the above process was carried out at temperatures between about 0° C and about 100° C. Preferably, the reaction was carried out at about rt. The above process was preferably carried out at or about atmospheric pressure although higher or lower pressures may be used if desired.
- Suitable solvents for use in the above process include, but are not limited to, ethers such as THF, glyme, and the like; DMF; DMSO; MeCN; halogenated solvents such as chloroform or DCM. If desired, mixtures of these solvents may be used, however the preferred solvents were DCM and DMF. The above process was carried out at temperatures between about 0° C and about 100° C.
- the reaction was carried out at or about rt.
- the above process was preferably carried out at about atmospheric pressure although higher or lower pressures may be used if desired.
- Substantially equimolar amounts of reactants were preferably used although higher or lower amounts may be used if desired.
- bases such as NaOH, TEA or DIPEA and the like in conjunction with DMAP and the like.
- Suitable solvents for use in this process included, but were not limited to, ethers such as THF, glyme, and the like; DMF; DMSO; MeCN; halogenated solvents such as chloroform or DCM; or alcohols or water.
- mixtures of these solvents may be used, however the preferred solvent was DCM.
- the above process was carried out at temperatures between about -20° C and about 40° C. Preferably, the reaction was carried out between 0° C and 25° C.
- the above process to produce was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially equimolar amounts of compounds of Formula III and IV and base and sub-stoichiometric amounts of
- DMAP were preferably used although higher or lower amounts may be used if desired.
- other suitable reaction conditions for the conversion of a carboxylic acid derived compound such as compound of Formula II to an amide such as compound of Formula I can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley and Sons: New York, 1999, pp 1941-1949.
- Compounds of Formula III and IV as well as lla are either commercially available, are synthesized by known chemical procedures or are described in detail within.
- HATU hexafluorophosphate
- N,N-diisopropylethylamine 83 mg, 0.64 mmol.
- the reaction was stirred for 2 hours befcfre it was quenched by addition of with ice-water (10 mL).
- the mixture was extracted with ethyl acetate (3 x 10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- HATU hexafluorophosphate
- N,N-diisopropylethylamine 3.0 g, 0.024 mol.
- the reaction was stirred for 2 hours before quenching with ice-water (10 mL).
- the mixture was extracted with ethyl acetate (3 ⁇ 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- phenylamino)azetidine-1 -carboxylate (90 mg, 0.21 mmol) in dichloromethane (5 mL) was added sequentially (f?)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (65 mg, 0.21 mmol), 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium- 3-oxide hexafluorophosphate (HATU) (260 mg, 0.68 mmol) and N,N-diisopropylethylamine (180 mg, 1 .36 mmol).
- HATU 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium- 3-oxide hexafluorophosphate
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Vascular Medicine (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Transplantation (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Diabetes (AREA)
- Gastroenterology & Hepatology (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (19)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2016013049A MX2016013049A (es) | 2014-04-04 | 2015-04-03 | Inhibidores de autotaxina espirociclicos sustituidos. |
US15/300,762 US10011601B2 (en) | 2014-04-04 | 2015-04-03 | Substituted spirocyclic inhibitors of autotaxin |
CU2016000150A CU24442B1 (es) | 2014-04-04 | 2015-04-03 | Derivados de n-(1-(espirocíclico)oxo) amida sustituidos como inhibidores de autotaxina |
AU2015240519A AU2015240519B2 (en) | 2014-04-04 | 2015-04-03 | Substituted spirocyclic inhibitors of autotaxin |
EP15773254.6A EP3125895A4 (en) | 2014-04-04 | 2015-04-03 | Substituted spirocydic inhibitors of autotaxin |
SG11201607920RA SG11201607920RA (en) | 2014-04-04 | 2015-04-03 | Substituted spirocyclic inhibitors of autotaxin |
MDA20160116A MD20160116A2 (ro) | 2014-04-04 | 2015-04-03 | Inhibitori spirociclici substituiţi ai autotaxinei |
EA201691840A EA201691840A1 (ru) | 2014-04-04 | 2015-04-03 | Замещенные спироциклические ингибиторы аутотаксина |
CN201580028170.3A CN107106559A (zh) | 2014-04-04 | 2015-04-03 | 自分泌运动因子的取代的螺环抑制剂 |
KR1020167030589A KR20160133004A (ko) | 2014-04-04 | 2015-04-03 | 오토탁신의 치환된 스피로시클릭 억제제 |
JP2017503794A JP6616821B2 (ja) | 2014-04-04 | 2015-04-03 | オートタキシンの置換スピロ環式阻害剤 |
CA2943874A CA2943874A1 (en) | 2014-04-04 | 2015-04-03 | Substituted spirocyclic inhibitors of autotaxin |
CR20160496A CR20160496A (es) | 2014-04-04 | 2015-04-03 | Inhibidores espirocíclicos sustituidos de la autotaxina |
AP2016009496A AP2016009496A0 (en) | 2014-04-04 | 2015-04-03 | Substituted spirocydic inhibitors of autotaxin |
IL248050A IL248050A0 (en) | 2014-04-04 | 2016-09-26 | Converted spirocyclics inhibit ototaxin |
PH12016501922A PH12016501922A1 (en) | 2014-04-04 | 2016-09-28 | Substituted spirocyclic inhibitors of autotaxin |
US15/896,905 US10233182B2 (en) | 2014-04-04 | 2018-02-14 | Substituted spirocyclic inhibitors of autotaxin |
US16/256,429 US20190225611A1 (en) | 2014-04-04 | 2019-04-12 | Substituted spirocyclic inhibitors of autotaxin |
AU2019264641A AU2019264641A1 (en) | 2014-04-04 | 2019-11-15 | Substituted spirocyclic inhibitors of autotaxin |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461975123P | 2014-04-04 | 2014-04-04 | |
US61/975,123 | 2014-04-04 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/300,762 A-371-Of-International US10011601B2 (en) | 2014-04-04 | 2015-04-03 | Substituted spirocyclic inhibitors of autotaxin |
US15/896,905 Continuation US10233182B2 (en) | 2014-04-04 | 2018-02-14 | Substituted spirocyclic inhibitors of autotaxin |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015154023A1 true WO2015154023A1 (en) | 2015-10-08 |
Family
ID=54241341
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2015/024338 WO2015154023A1 (en) | 2014-04-04 | 2015-04-03 | Substituted spirocydic inhibitors of autotaxin |
Country Status (21)
Country | Link |
---|---|
US (3) | US10011601B2 (ja) |
EP (1) | EP3125895A4 (ja) |
JP (2) | JP6616821B2 (ja) |
KR (1) | KR20160133004A (ja) |
CN (1) | CN107106559A (ja) |
AP (1) | AP2016009496A0 (ja) |
AU (2) | AU2015240519B2 (ja) |
CA (1) | CA2943874A1 (ja) |
CL (1) | CL2016002516A1 (ja) |
CR (1) | CR20160496A (ja) |
CU (1) | CU24442B1 (ja) |
DO (1) | DOP2016000270A (ja) |
EA (1) | EA201691840A1 (ja) |
EC (1) | ECSP16084293A (ja) |
IL (1) | IL248050A0 (ja) |
MD (1) | MD20160116A2 (ja) |
MX (1) | MX2016013049A (ja) |
PE (1) | PE20170206A1 (ja) |
PH (1) | PH12016501922A1 (ja) |
SG (1) | SG11201607920RA (ja) |
WO (1) | WO2015154023A1 (ja) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017152062A1 (en) | 2016-03-04 | 2017-09-08 | Gilead Sciences, Inc. | Compositions and combinations of autotaxin inhibitors |
US10011601B2 (en) | 2014-04-04 | 2018-07-03 | X-Rx, Inc. | Substituted spirocyclic inhibitors of autotaxin |
WO2018153312A1 (zh) * | 2017-02-22 | 2018-08-30 | 广州市恒诺康医药科技有限公司 | 氮杂螺环类化合物及其制备方法和应用 |
JP2020500178A (ja) * | 2016-11-16 | 2020-01-09 | ルンドベック ラ ホーヤ リサーチ センター,インク. | Magl阻害剤 |
US10633384B2 (en) | 2012-06-13 | 2020-04-28 | Hoffmann-La Roche Inc. | Diazaspirocycloalkane and azaspirocycloalkane |
US10640472B2 (en) | 2015-09-04 | 2020-05-05 | Hoffman-La Roche Inc. | Phenoxymethyl derivatives |
US10647719B2 (en) | 2015-09-24 | 2020-05-12 | Hoffmann-La Roche Inc. | Bicyclic compounds as dual ATX/CA inhibitors |
US10654857B2 (en) | 2014-03-26 | 2020-05-19 | Hoffman-La Roche Inc. | Bicyclic compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors |
US10669268B2 (en) | 2012-09-25 | 2020-06-02 | Hoffmann-La Roche Inc. | Bicyclic derivatives |
US10669285B2 (en) | 2014-03-26 | 2020-06-02 | Hoffmann-La Roche Inc. | Condensed [1,4] diazepine compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors |
US10676446B2 (en) | 2015-04-10 | 2020-06-09 | Hoffmann-La Roche Inc. | Bicyclic quinazolinone derivatives |
US10738053B2 (en) | 2015-09-24 | 2020-08-11 | Hoffmann-La Roche Inc. | Bicyclic compounds as dual ATX/CA inhibitors |
US10787459B2 (en) | 2015-09-24 | 2020-09-29 | Hoffmann-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US10800786B2 (en) | 2015-09-24 | 2020-10-13 | Hoffman-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US10849881B2 (en) | 2013-11-26 | 2020-12-01 | Hoffmann-La Roche Inc. | Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl |
US10882857B2 (en) | 2017-03-16 | 2021-01-05 | Hoffmann-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US10913745B2 (en) | 2013-03-12 | 2021-02-09 | Hoffmann-La Roche Inc. | Octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors |
US11059794B2 (en) | 2017-03-16 | 2021-07-13 | Hoffmann-La Roche Inc. | Heterocyclic compounds useful as dual ATX/CA inhibitors |
WO2022149010A1 (en) * | 2021-01-05 | 2022-07-14 | Cadila Healthcare Limited | Novel inhibitors of autotaxin |
US11434222B2 (en) | 2020-11-13 | 2022-09-06 | H. Lundbeck A/S | MAGL inhibitors |
WO2024073658A1 (en) * | 2022-09-30 | 2024-04-04 | Genentech, Inc. | Hydantoin modulators of cholesterol biosynthesis and their use for promoting remyelination |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10961242B2 (en) | 2017-05-17 | 2021-03-30 | Legochem Biosciences, Inc. | Compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same |
KR101798840B1 (ko) | 2017-05-17 | 2017-11-17 | 주식회사 레고켐 바이오사이언스 | 신규 오토탁신 저해 화합물 및 이를 함유하는 약제학적 조성물 |
WO2019065791A1 (ja) | 2017-09-29 | 2019-04-04 | 武田薬品工業株式会社 | 複素環化合物 |
WO2020051230A1 (en) * | 2018-09-04 | 2020-03-12 | X-Rx, Inc. | Amorphous pharmaceutical compositions and uses thereof |
CN112675308B (zh) * | 2020-12-09 | 2023-05-05 | 中国人民解放军军事科学院军事医学研究院 | 抑制enpp2基因和/或蛋白表达的物质在制备治疗多发性骨髓瘤的药物中的应用 |
Citations (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008021927A2 (en) * | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
US20080176883A1 (en) * | 2006-11-17 | 2008-07-24 | George Dawn M | Aminopyrrolidines as chemokine receptor antagonists |
WO2009151644A2 (en) | 2008-06-13 | 2009-12-17 | Yale University | Small molecule inhibitors of autotaxin methods of use |
US20100016258A1 (en) | 2008-01-09 | 2010-01-21 | University Of Virginia Patent Foundation | Phosphonate derivatives as autotaxin inhibitors |
WO2010063352A1 (en) | 2008-12-01 | 2010-06-10 | Merck Patent Gmbh | 2, 5-diamino-substituted pyrido [4, 3-d] pyrimidines as autotaxin inhibitors against cancer |
WO2010112124A1 (en) | 2009-04-02 | 2010-10-07 | Merck Patent Gmbh | Autotaxin inhibitors |
WO2010112116A1 (de) | 2009-04-02 | 2010-10-07 | Merck Patent Gmbh | Heterocyclische verbindungen als autotaxin-inhibitoren |
WO2010115491A2 (en) | 2009-04-02 | 2010-10-14 | Merck Patent Gmbh | Piperidine and piperazine derivatives as autotaxin inhibitors |
WO2010144646A2 (en) * | 2009-06-11 | 2010-12-16 | Abbott Laboratories | Anti-viral compounds |
WO2011006569A1 (de) | 2009-07-16 | 2011-01-20 | Merck Patent Gmbh | Heterocyclische verbindungen als autotaxin-inhibitoren |
WO2011017350A2 (en) | 2009-08-04 | 2011-02-10 | Amira Pharmaceuticals, Inc. | Compounds as lysophosphatidic acid receptor antagonists |
WO2011116867A1 (de) | 2010-03-26 | 2011-09-29 | Merck Patent Gmbh | Benzonaphthyridinamine als autotaxin-inhibitoren |
WO2012024620A2 (en) | 2010-08-20 | 2012-02-23 | Amira Pharmaceuticals, Inc. | Autotaxin inhibitors and uses thereof |
US20120100592A1 (en) | 2009-10-26 | 2012-04-26 | Abby Louise Parrill-Baker | Pipemidic acid derivative autotaxin inhibitors |
WO2012166415A1 (en) | 2011-05-27 | 2012-12-06 | Amira Pharmaceuticals, Inc. | Heterocyclic autotaxin inhibitors and uses thereof |
WO2013061297A1 (en) | 2011-10-28 | 2013-05-02 | Pfizer Limited | Pyridazine Derivatives Useful in Therapy |
WO2013186159A1 (en) | 2012-06-13 | 2013-12-19 | F. Hoffmann-La Roche Ag | New diazaspirocycloalkane and azaspirocycloalkane |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5877182A (en) | 1996-09-13 | 1999-03-02 | Merck & Co., Inc. | Piperidines promote release of growth hormone |
WO1998050534A1 (en) | 1997-05-08 | 1998-11-12 | Smithkline Beecham Corporation | Protease inhibitors |
GB0030303D0 (en) | 2000-12-13 | 2001-01-24 | Lilly Co Eli | Compounds |
CA2439691A1 (en) * | 2001-03-02 | 2002-09-12 | Bristol-Myers Squibb Company | Co-administration of melanocortin receptor agonist and phosphodiesterase inhibitor for treatment of cyclic-amp associated disorders |
CA2438272A1 (en) * | 2001-03-02 | 2002-10-10 | John Macor | Compounds useful as modulators of melanocortin receptors and pharmaceutical compositions comprising same |
NZ531870A (en) * | 2001-10-01 | 2005-08-26 | Bristol Myers Squibb Co | Spiro-hydantoin compounds useful as anti-inflammatory agents |
US20040192674A1 (en) | 2003-02-14 | 2004-09-30 | Marquis Robert W. | Cathepsin L inhibitors |
CA2512886A1 (en) | 2003-02-28 | 2004-09-10 | Galderma Research & Development, S.N.C. | Ligands that modulate lxr-type receptors |
WO2005122379A2 (en) * | 2004-05-27 | 2005-12-22 | The Regents Of The University Of California | Alpha-4 beta-1 integrin ligands for imaging and therapy |
JPWO2006137465A1 (ja) | 2005-06-24 | 2009-01-22 | 塩野義製薬株式会社 | 含窒素複素環誘導体 |
US7601844B2 (en) | 2006-01-27 | 2009-10-13 | Bristol-Myers Squibb Company | Piperidinyl derivatives as modulators of chemokine receptor activity |
US8906859B2 (en) * | 2006-11-10 | 2014-12-09 | Cera Therapeutics, Inc. | Uses of kappa opioid synthetic peptide amides |
JP2011518774A (ja) | 2008-03-20 | 2011-06-30 | フォレスト・ラボラトリーズ・ホールディングス・リミテッド | ステアロイル−CoAデサチュラーゼの阻害剤としての新規ピペリジン誘導体 |
WO2010037081A1 (en) * | 2008-09-29 | 2010-04-01 | Palatin Technologies, Inc. | Melanocortin receptor-specific spiro-piperidine compounds |
KR101184115B1 (ko) * | 2009-08-31 | 2012-09-18 | 일동제약주식회사 | 신규 펩티드 데포르밀라제 저해제 화합물 및 그 제조방법 |
US8518945B2 (en) | 2010-03-22 | 2013-08-27 | Hoffmann-La Roche Inc. | Pyrrolopyrazine kinase inhibitors |
JP2011219368A (ja) | 2010-04-02 | 2011-11-04 | Daiichi Sankyo Co Ltd | N−サリチルアミノ酸誘導体 |
US8546416B2 (en) * | 2011-05-27 | 2013-10-01 | Novartis Ag | 3-spirocyclic piperidine derivatives as ghrelin receptor agonists |
AR095079A1 (es) | 2013-03-12 | 2015-09-16 | Hoffmann La Roche | Derivados de octahidro-pirrolo[3,4-c]-pirrol y piridina-fenilo |
TW201500356A (zh) | 2013-04-12 | 2015-01-01 | Lilly Co Eli | 二氫吡啶并嘧啶化合物 |
EP3022201A1 (en) | 2013-07-18 | 2016-05-25 | Novartis AG | Autotaxin inhibitors |
TN2016000022A1 (en) | 2013-07-18 | 2017-07-05 | Novartis Ag | Autotaxin inhibitors comprising a heteroaromatic ring-benzyl-amide-cycle core |
JP2016530210A (ja) | 2013-09-17 | 2016-09-29 | ファーマケア,インク. | ヘテロ環式ビニルオートタキシン阻害剤化合物 |
EP3046905A4 (en) | 2013-09-17 | 2017-03-22 | Pharmakea Inc. | Vinyl autotaxin inhibitor compounds |
US9850203B2 (en) | 2013-09-26 | 2017-12-26 | Pharmakea, Inc. | Autotaxin inhibitor compounds |
CA2943874A1 (en) | 2014-04-04 | 2015-10-08 | X-Rx, Inc. | Substituted spirocyclic inhibitors of autotaxin |
CN107205972A (zh) | 2014-04-23 | 2017-09-26 | X-Rx股份有限公司 | 自分泌运动因子的取代的n‑(2‑(氨基)‑2‑氧代乙基)苯甲酰胺抑制剂及它们的制备和在治疗lpa‑依赖的或lpa‑介导的疾病中的用途 |
-
2015
- 2015-04-03 CA CA2943874A patent/CA2943874A1/en not_active Abandoned
- 2015-04-03 JP JP2017503794A patent/JP6616821B2/ja not_active Expired - Fee Related
- 2015-04-03 KR KR1020167030589A patent/KR20160133004A/ko unknown
- 2015-04-03 EP EP15773254.6A patent/EP3125895A4/en not_active Withdrawn
- 2015-04-03 AU AU2015240519A patent/AU2015240519B2/en not_active Ceased
- 2015-04-03 SG SG11201607920RA patent/SG11201607920RA/en unknown
- 2015-04-03 PE PE2016001885A patent/PE20170206A1/es unknown
- 2015-04-03 CN CN201580028170.3A patent/CN107106559A/zh active Pending
- 2015-04-03 EA EA201691840A patent/EA201691840A1/ru unknown
- 2015-04-03 CR CR20160496A patent/CR20160496A/es unknown
- 2015-04-03 AP AP2016009496A patent/AP2016009496A0/en unknown
- 2015-04-03 MD MDA20160116A patent/MD20160116A2/ro not_active Application Discontinuation
- 2015-04-03 US US15/300,762 patent/US10011601B2/en not_active Expired - Fee Related
- 2015-04-03 MX MX2016013049A patent/MX2016013049A/es unknown
- 2015-04-03 WO PCT/US2015/024338 patent/WO2015154023A1/en active Application Filing
- 2015-04-03 CU CU2016000150A patent/CU24442B1/es unknown
-
2016
- 2016-09-26 IL IL248050A patent/IL248050A0/en unknown
- 2016-09-28 PH PH12016501922A patent/PH12016501922A1/en unknown
- 2016-10-03 DO DO2016000270A patent/DOP2016000270A/es unknown
- 2016-10-04 CL CL2016002516A patent/CL2016002516A1/es unknown
- 2016-10-26 EC ECIEPI201684293A patent/ECSP16084293A/es unknown
-
2018
- 2018-02-14 US US15/896,905 patent/US10233182B2/en not_active Expired - Fee Related
-
2019
- 2019-04-12 US US16/256,429 patent/US20190225611A1/en not_active Abandoned
- 2019-11-08 JP JP2019203023A patent/JP2020040960A/ja active Pending
- 2019-11-15 AU AU2019264641A patent/AU2019264641A1/en not_active Abandoned
Patent Citations (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008021927A2 (en) * | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
US20080176883A1 (en) * | 2006-11-17 | 2008-07-24 | George Dawn M | Aminopyrrolidines as chemokine receptor antagonists |
US20100016258A1 (en) | 2008-01-09 | 2010-01-21 | University Of Virginia Patent Foundation | Phosphonate derivatives as autotaxin inhibitors |
WO2009151644A2 (en) | 2008-06-13 | 2009-12-17 | Yale University | Small molecule inhibitors of autotaxin methods of use |
WO2010063352A1 (en) | 2008-12-01 | 2010-06-10 | Merck Patent Gmbh | 2, 5-diamino-substituted pyrido [4, 3-d] pyrimidines as autotaxin inhibitors against cancer |
WO2010112124A1 (en) | 2009-04-02 | 2010-10-07 | Merck Patent Gmbh | Autotaxin inhibitors |
WO2010112116A1 (de) | 2009-04-02 | 2010-10-07 | Merck Patent Gmbh | Heterocyclische verbindungen als autotaxin-inhibitoren |
WO2010115491A2 (en) | 2009-04-02 | 2010-10-14 | Merck Patent Gmbh | Piperidine and piperazine derivatives as autotaxin inhibitors |
WO2010144646A2 (en) * | 2009-06-11 | 2010-12-16 | Abbott Laboratories | Anti-viral compounds |
WO2011006569A1 (de) | 2009-07-16 | 2011-01-20 | Merck Patent Gmbh | Heterocyclische verbindungen als autotaxin-inhibitoren |
WO2011017350A2 (en) | 2009-08-04 | 2011-02-10 | Amira Pharmaceuticals, Inc. | Compounds as lysophosphatidic acid receptor antagonists |
US20120100592A1 (en) | 2009-10-26 | 2012-04-26 | Abby Louise Parrill-Baker | Pipemidic acid derivative autotaxin inhibitors |
WO2011116867A1 (de) | 2010-03-26 | 2011-09-29 | Merck Patent Gmbh | Benzonaphthyridinamine als autotaxin-inhibitoren |
WO2012024620A2 (en) | 2010-08-20 | 2012-02-23 | Amira Pharmaceuticals, Inc. | Autotaxin inhibitors and uses thereof |
WO2012166415A1 (en) | 2011-05-27 | 2012-12-06 | Amira Pharmaceuticals, Inc. | Heterocyclic autotaxin inhibitors and uses thereof |
WO2013061297A1 (en) | 2011-10-28 | 2013-05-02 | Pfizer Limited | Pyridazine Derivatives Useful in Therapy |
WO2013186159A1 (en) | 2012-06-13 | 2013-12-19 | F. Hoffmann-La Roche Ag | New diazaspirocycloalkane and azaspirocycloalkane |
Non-Patent Citations (5)
Title |
---|
DATABASE PUBCHEM. [o] 24 January 2012 (2012-01-24), XP055359190, Database accession no. 55023722 * |
DATABASE PUBCHEM. [o] 8 March 2012 (2012-03-08), Database accession no. 56755867 * |
See also references of EP3125895A4 |
T. W. GREENE: "Compendium of Organic Synthetic Methods", vol. I-VI, 1981, WILEY-LNTERSCIENCE |
T. W. GREENEP. G. M. WUTS: "Protective Groups in Organic Chemistry", 1999, JOHN WILEY & SONS, pages: 1941 - 1949 |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10633384B2 (en) | 2012-06-13 | 2020-04-28 | Hoffmann-La Roche Inc. | Diazaspirocycloalkane and azaspirocycloalkane |
US10669268B2 (en) | 2012-09-25 | 2020-06-02 | Hoffmann-La Roche Inc. | Bicyclic derivatives |
US10913745B2 (en) | 2013-03-12 | 2021-02-09 | Hoffmann-La Roche Inc. | Octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors |
US10849881B2 (en) | 2013-11-26 | 2020-12-01 | Hoffmann-La Roche Inc. | Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl |
US11098048B2 (en) | 2014-03-26 | 2021-08-24 | Hoffmann-La Roche Inc. | Bicyclic compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors |
US10654857B2 (en) | 2014-03-26 | 2020-05-19 | Hoffman-La Roche Inc. | Bicyclic compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors |
US10669285B2 (en) | 2014-03-26 | 2020-06-02 | Hoffmann-La Roche Inc. | Condensed [1,4] diazepine compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors |
US10011601B2 (en) | 2014-04-04 | 2018-07-03 | X-Rx, Inc. | Substituted spirocyclic inhibitors of autotaxin |
US10233182B2 (en) | 2014-04-04 | 2019-03-19 | X-Rx, Inc. | Substituted spirocyclic inhibitors of autotaxin |
US10676446B2 (en) | 2015-04-10 | 2020-06-09 | Hoffmann-La Roche Inc. | Bicyclic quinazolinone derivatives |
US11352330B2 (en) | 2015-09-04 | 2022-06-07 | Hoffmann-La Roche Inc. | Phenoxymethyl derivatives |
US10640472B2 (en) | 2015-09-04 | 2020-05-05 | Hoffman-La Roche Inc. | Phenoxymethyl derivatives |
US10800786B2 (en) | 2015-09-24 | 2020-10-13 | Hoffman-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US10738053B2 (en) | 2015-09-24 | 2020-08-11 | Hoffmann-La Roche Inc. | Bicyclic compounds as dual ATX/CA inhibitors |
US10787459B2 (en) | 2015-09-24 | 2020-09-29 | Hoffmann-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US10889588B2 (en) | 2015-09-24 | 2021-01-12 | Hoffmann-La Roche Inc. | Bicyclic compounds as dual ATX/CA inhibitors |
US10647719B2 (en) | 2015-09-24 | 2020-05-12 | Hoffmann-La Roche Inc. | Bicyclic compounds as dual ATX/CA inhibitors |
WO2017152062A1 (en) | 2016-03-04 | 2017-09-08 | Gilead Sciences, Inc. | Compositions and combinations of autotaxin inhibitors |
US11691975B2 (en) | 2016-11-16 | 2023-07-04 | H. Lundbecka/S | MAGL inhibitors |
JP2020500178A (ja) * | 2016-11-16 | 2020-01-09 | ルンドベック ラ ホーヤ リサーチ センター,インク. | Magl阻害剤 |
JP7042468B2 (ja) | 2016-11-16 | 2022-03-28 | ルンドベック ラ ホーヤ リサーチ センター,インク. | Magl阻害剤 |
WO2018153312A1 (zh) * | 2017-02-22 | 2018-08-30 | 广州市恒诺康医药科技有限公司 | 氮杂螺环类化合物及其制备方法和应用 |
US10882857B2 (en) | 2017-03-16 | 2021-01-05 | Hoffmann-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US11673888B2 (en) | 2017-03-16 | 2023-06-13 | Hoffmann-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US11059794B2 (en) | 2017-03-16 | 2021-07-13 | Hoffmann-La Roche Inc. | Heterocyclic compounds useful as dual ATX/CA inhibitors |
US11434222B2 (en) | 2020-11-13 | 2022-09-06 | H. Lundbeck A/S | MAGL inhibitors |
WO2022149010A1 (en) * | 2021-01-05 | 2022-07-14 | Cadila Healthcare Limited | Novel inhibitors of autotaxin |
WO2024073658A1 (en) * | 2022-09-30 | 2024-04-04 | Genentech, Inc. | Hydantoin modulators of cholesterol biosynthesis and their use for promoting remyelination |
Also Published As
Publication number | Publication date |
---|---|
PH12016501922A1 (en) | 2016-12-19 |
SG11201607920RA (en) | 2016-10-28 |
AU2019264641A1 (en) | 2019-12-05 |
EP3125895A1 (en) | 2017-02-08 |
JP2017513932A (ja) | 2017-06-01 |
US20190225611A1 (en) | 2019-07-25 |
PE20170206A1 (es) | 2017-04-09 |
EA201691840A1 (ru) | 2017-03-31 |
KR20160133004A (ko) | 2016-11-21 |
CR20160496A (es) | 2017-01-02 |
MD20160116A2 (ro) | 2017-04-30 |
US10011601B2 (en) | 2018-07-03 |
US20180282332A1 (en) | 2018-10-04 |
JP6616821B2 (ja) | 2019-12-04 |
AU2015240519B2 (en) | 2019-08-15 |
DOP2016000270A (es) | 2016-12-15 |
US20170166568A1 (en) | 2017-06-15 |
US10233182B2 (en) | 2019-03-19 |
CN107106559A (zh) | 2017-08-29 |
CA2943874A1 (en) | 2015-10-08 |
MX2016013049A (es) | 2017-04-27 |
CU24442B1 (es) | 2019-09-04 |
CL2016002516A1 (es) | 2017-05-12 |
AP2016009496A0 (en) | 2016-10-31 |
IL248050A0 (en) | 2016-11-30 |
CU20160150A7 (es) | 2017-02-02 |
JP2020040960A (ja) | 2020-03-19 |
EP3125895A4 (en) | 2017-08-30 |
AU2015240519A1 (en) | 2016-10-20 |
ECSP16084293A (es) | 2017-01-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10233182B2 (en) | Substituted spirocyclic inhibitors of autotaxin | |
CA2683695C (en) | 3-amido-pyrrolo[3,4-c]pyrazole-5(1h,4h,6h) carbaldehyde derivatives | |
AU2014225604B2 (en) | Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use | |
JP6592008B2 (ja) | オートタキシンの置換n−(2−アミノ)−2−オキソエチルベンズアミド阻害剤およびそれらの調製、ならびにlpa依存性またはlpa媒介性疾患の処置における使用 | |
AU2017311645A1 (en) | Pyridopyrimdinone CDK2/4/6 inhibitors | |
AU2019228568B2 (en) | Piperidinyl-3-(aryloxy)propanamides and propanoates | |
CA2937210A1 (en) | 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives and 1,1,1-trifluoro-4-hydroxybutan-2-yl carbamate derivatives | |
UA114323C2 (uk) | Інгібітори nampt | |
CA3053484A1 (en) | Aminotriazolopyridines as kinase inhibitors | |
CA2859578A1 (en) | Dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders. | |
CA2509711A1 (en) | Piperidine derivatives as ccr5 antagonists | |
CA3082156A1 (en) | Heterocyclic compound as a protein kinase inhibitor | |
KR20210049895A (ko) | 고 활성 sting 단백질 작용제 화합물 | |
JP6322275B2 (ja) | ヤヌスキナーゼ阻害剤としてのn−(2−シアノヘテロシクリル)ピラゾロピリドン | |
TW202122382A (zh) | 乙內醯脲衍生物 | |
JP2019522018A (ja) | コリンキナーゼ阻害剤としてのプリン及び3−デアザプリンアナログ | |
JP7551607B2 (ja) | アデノシン受容体アンタゴニストとしての5-アザインダゾール誘導体 | |
JP2023509495A (ja) | RORγt阻害剤、その製造方法及び使用 | |
KR102133595B1 (ko) | 단백질 키나제 억제제로서의 헤테로고리 화합물 | |
OA18996A (en) | Substituted Spirocyclic Inhibitors of Autotaxin | |
KR102112336B1 (ko) | 단백질 키나제 억제제로서의 헤테로고리 화합물 | |
RU2783723C2 (ru) | Гетероциклическое соединение в качестве ингибитора протеинкиназы | |
CA3219215A1 (en) | Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use | |
NZ787918A (en) | Pyridopyrimdinone CDK2/4/6 inhibitors | |
EA041386B1 (ru) | Спироциклические соединения и способы их получения и применения |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15773254 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2943874 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 248050 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12016501922 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15300762 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 2017503794 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 001885-2016 Country of ref document: PE |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: NC2016/0002679 Country of ref document: CO Ref document number: MX/A/2016/013049 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: A201610387 Country of ref document: UA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201691840 Country of ref document: EA |
|
ENP | Entry into the national phase |
Ref document number: 2015240519 Country of ref document: AU Date of ref document: 20150403 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: CR2016-000496 Country of ref document: CR |
|
ENP | Entry into the national phase |
Ref document number: 20160116 Country of ref document: MD Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: A 2016 0116 Country of ref document: MD |
|
ENP | Entry into the national phase |
Ref document number: 20167030589 Country of ref document: KR Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112016022801 Country of ref document: BR |
|
REEP | Request for entry into the european phase |
Ref document number: 2015773254 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015773254 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 112016022801 Country of ref document: BR Kind code of ref document: A2 Effective date: 20160930 |